Kristallstrukturen mit kleinen Sondenmolekülen: Ausleuchten von Bindetaschen, Startpunkt für ein Fragment-basiertes Wirkstoffdesign und Erhalten von Phaseninformationen zur Strukturlösung

Im Zuge dieser Doktorarbeit wurden unterschiedliche Bereiche behandelt, in denen die Proteinkristallographie wichtige Beiträge liefert. Angefangen bei der de novo Strukturaufklärung von Makromolekülen über Fragmentscreening mittels Röntgenstrukturanalyse bis hin zur strukturbasierten Entwicklung neu...

Ausführliche Beschreibung

Gespeichert in:
1. Verfasser: Behnen, Jürgen
Beteiligte: Klebe, Gerhard (Prof.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Deutsch
Veröffentlicht: Philipps-Universität Marburg 2011
Pharmazeutische Chemie
Ausgabe:http://dx.doi.org/10.17192/z2011.0076
Schlagworte:
Online Zugang:PDF-Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!

1. Laemmli, U. K. (1970). "Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4." Nature 227(5259): 680-685.


2. Gasteiger, E., Gattiker, A., Hoogland, C., Ivanyi, I., Appel, R. D. and Bairoch, A. (2003). "ExPASy: the proteomics server for in-depth protein knowledge and analysis." Nucleic Acids Research. 31(13): 3784-3788.


3. Soltis, S. M., Stowell, M. H. B., Wiener, M. C., Phillips, G. N. and Rees, D. C. (1997). "Successful flash-cooling of xenon-derivatized myoglobin crystals." Journal of Applied Crystallography 30(2): 190-194.


4. Chang, C., Park, B. C., Lee, D.-S. and Suh, S. W. (1999). "Crystal structures of thermostable xylose isomerases from Thermus caldophilus and Thermus thermophilus: possible structural determinants of thermostability." Journal of Molecular Biology 288(4): 623-634.


5. Sussman, J. L., Harel, M., Frolow, F., Varon, L., Toker, L., Futerman, A. H. and Silman, I. (1988). "Purification and crystallization of a dimeric form of acetylcholinesterase from Torpedo californica subsequent to solubilization with phosphatidylinositol-specific phospholipase C." Journal of Molecular Biology 203(3): 821-823.


6. Cohen, A., Ellis, P., Kresge, N. and Soltis, M. S. (2001). "MAD phasing with krypton." Acta Crystallographica Section D 57(2): 233-238.


7. Brunger, A. T. (1998). "Crystallography and NMR System (CNS): a new software system for macromolecular structure determination." Acta Crystallog. D 54: 905-921.


8. Dauter, Z., Dauter, M. and Dodson, E. (2002). "Jolly SAD." Acta Crystallographica Section D 58(3): 494-506.


9. Stengl, B., Meyer, E. A., Heine, A., Brenk, R., Diederich, F. and Klebe, G. (2007). "Crystal Structures of tRNA-guanine Transglycosylase (TGT) in Complex with Novel and Potent Inhibitors Unravel Pronounced Induced-fit Adaptations and Suggest Dimer Formation Upon Substrate Binding." Journal of Molecular Biology 370(3): 492-511.


10. Morihara, K. (1967). "The specificities of various neutral and alkaline proteinases from microorganisms." Biochemical and Biophysical Research Communications 26(6): 656-661.


11. Romier, C., Meyer, J. E. W. and Suck, D. (1997). "Slight sequence variations of a common fold explain the substrate specificities of tRNA-guanine transglycosylases from the three kingdoms." FEBS Letters 416(1): 93-98.


12. Abad-Zapatero, C. and Metz, J. T. (2005). "Ligand efficiency indices as guideposts for drug discovery." Drug Discovery Today 10(7): 464-469.


13. Xie, W., Liu, X. and Huang, R. (2003). "Chemical trapping and crystal structure of a catalytic tRNA guanine transglycosylase covalent intermediate." Nature Structural Molecular Biolology 10: 781-788.


14. English, A. C., Groom, C. R. and Hubbard, R. E. (2001). "Experimental and computational mapping of the binding surface of a crystalline protein." Protein Engineering. 14(1): 47-59.


15. Mueller, M. (2002). Molekular-Dynamik-Simulationen zum Katalyse-Mechanismus der Acetylcholinesterase. Ph D Thesis, Georg-August-Universität Göttingen.


16. Kabsch, W. (1993). "Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants." Journal of Applied Crystallography 26(6): 795-800.


17. Lambeir, A. M., Lauwereys, M., Stanssens, P., Mrabet, N. T., Snauwaert, J., Van Tilbeurgh, H., Matthyssens, G., Lasters, I. and De Maeyer, M. (1992). "Protein engineering of xylose (glucose) isomerase from Actinoplanes missouriensis. 2. Site-directed mutagenesis of the xylose binding site." Biochemistry 31(24): 5459-5466.


18. Schiltz, M., Prange, T. and Fourme, R. (1994). "On the preparation and X-ray data collection of isomorphous xenon derivatives." Journal of Applied Crystallography 27(6): 950-960.


19. Schiltz, M., Fourme, R., Broutin, I. and Prangé, T. (1995). "The catalytic site of serine proteinases as a specific binding cavity for xenon." Structure 3(3): 309-316.


20. Prangé, T., Schiltz, M., Pernot, L., Colloc'h, N., Longhi, S., Bourguet, W. and Fourme, R. (1998). "Exploring hydrophobic sites in proteins with xenon or krypton." Proteins: Structure, Function, and Genetics 30(1): 61-73.


21. Houghton, P. J., Ren, Y. and Howes, M.-J. (2006). "Acetylcholinesterase inhibitors from plants and fungi." Natural Product Reports 23(2): 181-199.


22. Vonrhein, C., Blanc, E., Roversi, P. and Bricogne, G. (2007). "Automated structure solution with autoSHARP." Methods in Enzymology 364: 215 -230.


23. McDonnell, J. M. (2001). "Surface plasmon resonance: towards an understanding of the mechanisms of biological molecular recognition " Curr. Opin. Chem. Biol. 5(5): 572-577.


24. Knighton, D. R., Bell, S. M., Zheng, J., Ten Eyck, L. F., Xuong, N., Taylor, S. S. and Sowadski, J. M. (1993). "2.0 Å refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with a peptide inhibitor and detergent." Acta Crystallographica Section D 49(3): 357-361.


25. Zheng, J., Trafny, E. A., Knighton, D. R., Xuong, N., Taylor, S. S., Ten Eyck, L. F. and Sowadski, J. M. (1993). "2.2 A refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor." Acta Crystallographica Section D 49(3): 362-365.


26. Bourne, Y., Taylor, P. and Marchot, P. (1995). "Acetylcholinesterase inhibition by fasciculin: Crystal structure of the complex." Cell 83(3): 503-512.


27. Goodford, P. J. (1985). "A computational procedure for determining energetically favorable binding sites on biologically important macromolecules." Journal of Medicinal Chemistry 28(7): 849-857.


28. Hajduk, P. J. and Greer, J. (2007). "A decade of fragment-based drug design: strategic advances and lessons learned." Nat. Rev. Drug Discovery 6(3): 211.


29. Stroud, R. M. (1974). "A family of protein-cutting proteins." Scientific American 231: 74-88.


30. Tilton, R. J. (1988). "A fixture for X-ray crystallographic studies of biomolecules under high gas pressure." Journal of Applied Crystallography 21(1): 4-10.


31. Whitlow, M., Howard, A., J. , Finzel, B., C. , Poulos, T., L. , Winborne, E. and Gilliland, G. L. (1991). "A metal-mediated hydride shift mechanism for xylose isomerase based on the 1.6 Å Streptomycs rubiginosus structure with xylitol and D-xylose." Proteins: Structure, Function, and Genetics 9(3): 153-173.


32. Banbula, A., Potempa, J., Travis, J., Fernandez-Catalén, C., Mann, K., Huber, R., Bode, W. and Medrano, F. J. (1998). "Amino-acid sequence and three-dimensional structure of the Staphylococcus aureus metalloproteinase at 1.72 Å resolution." Structure 6(9): 1185-1193.


33. Ramachandran, G. N. and Raman, S. (1956). "A New Method for the Structure Analysis of Non-Centrosymmetric Crystals." Current Science 25: 348-351.


34. Allen, K. N., Bellamacina, C. R., Ding, X., Jeffrey, C. J. and Mattos, C. (1996). "An Experimental Approach to Mapping the Binding Surfaces of Crystalline Proteins." The Journal of Physical Chemistry 100(7): 2605 -2611.


35. Congreve, M., Carr, R., Murray, C. and Jhoti, H. (2003). "A `Rule of Three' for fragment-based lead discovery?" Drug Discovery Today 8(19): 876-877.


36. Sheldrick, G. (2008). "A short history of SHELX." Acta Crystallographica Section A 64(1): 112-122.


37. Stowell, M. H. B., Soltis, S. M., Kisker, C., Peters, J. W., Schindelin, H., Rees, D. C., Cascio, D., Beamer, L., Hart, P. J., Wiener, M. C. and Whitby, F. G. (1996). "A simple device for studying macromolecular crystals under moderate gas pressures (0.1-10 MPa)." Journal of Applied Crystallography 29(5): 608-613.


38. Kendrew, J. C., Bodo, G., Dintzis, H. M., Parrish, R. G., Wyckoff, H. and Phillips, D. C. (1958). "A Three-Dimensional Model of the Myoglobin Molecule Obtained by X-Ray Analysis." Nature 181(4610): 662-666.


39. Sussman, J. L., Harel, M., Frolow, F., Oefner, C., Goldman, A., Toker, L. and Silman, I. (1991). "Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein." Science 253(5022): 872-879.


40. Perrakis, A., Morris, R. and Lamzin, V. S. (1999). "Automated protein model building combined with iterative structure refinement." Nature Structural Mololecular Biology. 6(5): 458-463.


41. Smith, J. A., Francis, S. H. and Corbin, J. D. (1993). "Autophosphorylation: a salient feature of protein kinases." Molecular and Cellular Biochemistry 127(1): 51-70.


42. Schoenborn, B. P., Watson, H. C. and Kendrew, J. C. (1965). "Binding of Xenon to Sperm Whale Myoglobin." Nature 207(4992): 28-30.


43. Vieille, C., Epting, K., L. , Kelly, R., M. and Zeikus, J. G. (2001). "Bivalent cations and amino-acid composition contribute to the thermostability of Bacillus licheniformis xylose isomerase." European Journal of Biochemistry 268(23): 6291-6301.


44. Gill, S. C. and von Hippel, P. H. (1989). "Calculation of protein extinction coefficients from amino acid sequence data." Analytical Biochemistry 182(2): 319-326.


45. Taylor, S. S., Buechler, J. A. and Yonemoto, W. (1990). "Camp-Dependent Protein Kinase: Framework for a Diverse Family of Regulatory Enzymes." Annual Review of Biochemistry 59(1): 971-1005.


46. Tilton, R. F., Kuntz, I. D. and Petsko, G. A. (1984). "Cavities in proteins: structure of a metmyoglobin xenon complex solved to 1.9 Α." Biochemistry 23(13): 2849- 2857.


47. Carlson, C. R., Witczak, O., Vossebein, L., Labbe, J.-C., Skalhegg, B. S., Keryer, G., Herberg, F. W., Collas, P. and Tasken, K. (2001). "CDK1-mediated phosphorylation of the RII α regulatory subunit of PKA works as a molecular switch that promotes dissociation of RII α from centrosomes at mitosis." Journal of Cell Science 114(18): 3243-3254.


48. Feldmann, S. D., Sahm, H. and Sprenger, G. A. (1992). "Cloning and expression of the genes for xylose isomerase and xylulokinase from Klebsiella pneumoniae 1033 in Escherichia coli K12." Molecular Genetics and Genomics. 234(2): 201-210.


49. Bor, Y.-C., Moraes, C., Lee, S.-P., Crosby, W. L., Sinskey, A. J. and Batt, C. A. (1992). "Cloning and sequencing the Lactobacillus brevis gene encoding xylose isomerase." Gene 114(1): 127-132.


50. Collaborative Computational Project Number, n. (1994). "Collaborative Computational Project Number 4. The CCP4 suite: programs for protein crystallography." Acta Crystallographica Section D 50: 760.


51. Bourne, Y., Grassi, J., Bougis, P. E. and Marchot, P. (1999). "Conformational Flexibility of the Acetylcholinesterase Tetramer Suggested by X-ray Crystallography." Journal of Biological Chemistry 274(43): 30370-30376.


52. Hope, H. (1988). "Cryocrystallography of biological macromolecules: a generally applicable method." Acta Crystallographica Section B 44(1): 22-26.


53. Rasmussen, H., Cour, T. l., Nyborg, J. and Schulein, M. (1994). "Crystallization and preliminary investigation of xylose isomerase from Bacillus coagulans." Acta Crystallographica Section D 50(2): 231-233.


54. McPherson, A. (1999). "Crystallization of Biological Macromolecules." Cold Spring Harbor Laboratory Press 2nd.


55. Zheng, J., Knighton, D. R., Parello, J., Taylor, S. S., Sowadski, J. M., Tony, H. and Bartholomew, M. S. (1991). crystallization of catalytic subunit of adenosine cyclic monophosphate-dependent protein kinase. Methods in Enzymology, Academic Press. Volume 200: 508-521.


56. Zheng, J. H., Knighton, D. R., Xuong, N. H., Parello, J., Taylor, S. S. and Sowadski, J. M. (1992). "Crystallization studies of the catalytic subunit of cAMP-dependent protein kinase: crystals of murine recombinant catalytic subunit and a mutant, Cys /Ser 343, diffract to 2.7 A resolution." Acta Crystallographica Section B 48(2): 241-244.


57. Kester, W. R. and Matthews, B. W. (1977). "Crystallographic study of the binding of dipeptide inhibitors to thermolysin: implications for the mechanism of catalysis." Biochemistry 16(11): 2506-2516.


58. Orts, J., Tuma, J., Reese, M., Grimm, S. K., Monecke, P., Bartoschek, S., Schiffer, A., Wendt, K. U., Griesinger, C. and Carlomagno, T. (2008). "Crystallography- Independent Determination of Ligand Binding Modes13." Angewandte Chemie International Edition 47(40): 7736-7740.


59. Romier, C., Reuter, K., Suck, D. and Ficner, R. (1996). "Crystal structure of tRNA- guanine transglycosylase: RNA modification by base exchange." EMBO J. 15(11): 2850-2857.


60. Cowtan, K. D. and Zhang, K. Y. J. (1999). "Density modification for macromolecular phase improvement " Progress in Biophysics and Molecular Biology 72(3): 245.


61. Whittaker, M., Floyd, C. D., Brown, P. and Gearing, A. J. H. (1999). "Design and Therapeutic Application of Matrix Metalloproteinase Inhibitors." Chemical Reviews 99(9): 2735-2776.


62. Monod, M., Hube, B., Hess, D. and Sanglard, D. (1998). "Differential regulation of SAP8 and SAPS, which encode two new members of the secreted aspartic proteinase family in Candida albicans." Microbiology 144(10): 2731-2737.


63. Shuker, S. B., Hajduk, P. J., Meadows, R. P. and Fesik, S. W. (1996). "Discovering High-Affinity Ligands for Proteins: SAR by NMR." Science 274(5292): 1531- 1534.


64. Nienaber, V. L., Richardson, P. L., Klighofer, V., Bouska, J. J., Giranda, V. L. and Greer, J. (2000). "Discovering novel ligands for macromolecules using X-ray crystallographic screening." Nature Biotechnology. 18(10): 1105-1108.


65. Geschwindner, S., Olsson, L.-L., Albert, J. S., Deinum, J., Edwards, P. D., de Beer, T. and Folmer, R. H. A. (2007). "Discovery of a Novel Warhead against β- Secretase through Fragment-Based Lead Generations." Journal of Medicinal Chemistry 50(24): 5903-5911.


66. Lipinski, C. A. (2000). "Drug-like properties and the causes of poor solubility and poor permeability." Journal of Pharmacological and Toxicological Methods 44(1): 235-249.


67. Velec, H. F. G., Gohlke, H. and Klebe, G. (2005). "DrugScoreCSDKnowledge-Based Scoring Function Derived from Small Molecule Crystal Data with Superior Recognition Rate of Near-Native Ligand Poses and Better Affinity Prediction." Journal of Medicinal Chemistry 48(20): 6296-6303.


68. "D-Xylose isomerase from Streptomyces violaceoruber: Structural and catalytic roles of bivalent metal ions." Enzyme and Microbial Technology 10(11): 695- 700.


69. Hochster, R. M. and Watson, R. W. (1954). "Enzymatic isomerization of D-xylose to D- xylulose." Archives of Biochemistry and Biophysics 48(1): 120-129.


70. Koelsch, G., Tang, J., Loy, J. A., Monod, M., Jackson, K., Foundling, S. I. and Lin, X. (2000). "Enzymic characteristics of secreted aspartic proteases of Candida albicans." Biochimica et Biophysica Acta (BBA) -Protein Structure and Molecular Enzymology 1480(1-2): 117-131.


71. Uhler, M. D., Chrivia, J. C. and McKnight, G. S. (1986). "Evidence for a second isoform of the catalytic subunit of cAMP-dependent protein kinase." Journal of Biological Chemistry 261(33): 15360-15363.


72. Erlanson, D. A., McDowell, R. S. and O´Brien, T. (2004). "Fragment-Based Drug Discovery." Journal of Medicinal Chemistry. 47(14): 3463-3482.


73. Broach, J. R. and Thorner, J. (1996). "High-throughput screening for drug discovery." Nature 384(6604, suppl.): 14-16.


74. Pape, T. and Schneider, T. R. (2004). "HKL2MAP: a graphical user interface for macromolecular phasing with SHELX programs." Journal of Applied Crystallography 37(5): 843-844.


75. Warshel, A., Naray-Szabo, G., Sussman, F. and Hwang, J. K. (1989). "How do serine proteases really work?" Biochemistry 28(9): 3629-3637.


76. Gruber, A., Speth, C., Lukasser-Vogl, E., Zangerle, R., Borg-von Zepelin, M., Dierich, M. P. and Würzner, R. (1999). "Human immunodeficiency virus type 1 protease inhibitor attenuates Candida albicans virulence properties in vitro." Immunopharmacology 41(3): 227-234.


77. Jomaa, H., Wiesner, J., Sanderbrand, S., Altincicek, B., Weidemeyer, C., Hintz, M., Türbachova, I., Eberl, M., Zeidler, J., Lichtenthaler, H. K., Soldati, D. and Beck, E. (1999). "Inhibitors of the Nonmevalonate Pathway of Isoprenoid Biosynthesis as Antimalarial Drugs." Science 285(5433): 1573-1576.


78. Taylor, P. and Lappi, S. (1975). "Interaction of fluorescence probes with acetylcholinesterase. Site and specificity of propidium binding." Biochemistry 14(9): 1989-1997.


79. Hasinoff, B. B. (1982). "Kinetics of acetylthiocholine binding to electric eel acetylcholinesterase in glycerol/water solvents of increased viscosity Evidence for a diffusion-controlled reaction." Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 704(1): 52-58.


80. Gohlke, H., Hendlich, M. and Klebe, G. (2000). "Knowledge-based scoring function to predict protein-ligand interactions." Journal of Molecular Biology 295(2): 337- 356.


81. Hopkins, A. L., Groom, C. R. and Alex, A. (2004). "Ligand efficiency: a useful metric for lead selection." Drug Discovery Today 9(10): 430-431.


82. Stengl, B., Reuter, K. and Klebe, G. (2005). "Mechanism and Substrate Specificity of tRNA-Guanine Transglycosylases (TGTs): tRNA-Modifying Enzymes from the Three Different Kingdoms of Life Share a Common Catalytic Mechanism." ChemBioChem 6(11): 1926-1939.


83. Nordberg, A. (2006). "Mechanisms Behind the Neuroprotective Actions of Cholinesterase Inhibitors in Alzheimer Disease." Alzheimer Disease & Associated Disorders 20: 12-18.


84. Harrison, R. K., Chang, B., Niedzwiecki, L. and Stein, R. L. (1992). "Mechanistic studies on the human matrix metalloproteinase stromelysin." Biochemistry 31(44): 10757-10762.


85. Metz, G., Ottleben, H. and Vetter, D., Eds. (2003). Methods and Principles in Medicinal Chemistry.


86. Abrahams, J. P. and Leslie, A. G. W. (1996). "Methods used in the structure determination of bovine mitochondrial F 1 ATPase." Acta Crystallographica Section D 52(1): 30-42.


87. Carrell, H. L., Hoier, H. and Glusker, J. P. (1994). "Modes of binding substrates and their analogues to the enzyme d-xylose isomerase." Acta Crystallographica Section D 50(2): 113-123.


88. Sambrock, J. (1989). "Molecular cloning. ." A Labaratory Manual 2.


89. "Molecular Forces in Anesthesia." Advances in Pharmacology Volume 5: 1-2, 2A, 2B, 3-17.


90. Lichtenthaler, H. K. (2000). "Non-mevalonate isoprenoid biosynthesis: enzymes, genes and inhibitors." Biochem. Soc. Trans. 28(6): 785-789.


91. Taskén, K., Skâhegg, B. S., Solberg, R., Andersson, K. B., Taylor, S. S., Lea, T., Blomhoff, H. K., Jahnsen, T. and Hansson, V. (1993). "Novel isozymes of cAMP-dependent protein kinase exist in human cells due to formation of RI alpha-RI beta heterodimeric complexes." Journal of Biological Chemistry 268(28): 21276-21283.


92. Hohwy, M., Spadola, L., Lundquist, B., Hawtin, P., Dahmén, J., Groth-Clausen, I., Nilsson, E., Persdotter, S., von Wachenfeldt, K., Folmer, R. H. A. and Edman, K. (2008). "Novel Prostaglandin D Synthase Inhibitors Generated by Fragment- Based Drug Design " Journal of Medicinal Chemistry 51(7): 2178-2186.


93. Hubbard, M. J. and Cohen, P. (1993). "On target with a new mechanism for the regulation of protein phosphorylation." Trends in Biochemical Sciences 18(5): 172-177.


94. Mueller-Dieckmann, C., Panjikar, S., Tucker, P. A. and Weiss, M. S. (2005). "On the routine use of soft X-rays in macromolecular crystallography. Part III. The optimal data-collection wavelength." Acta Crystallographica Section D 61(9): 1263-1272.


95. Schechter, I. and Berger, A. (1967). "On the size of the active site in proteases. I. Papain." Biochemical and Biophysical Research Communications 27(2): 157- 162.


96. James, R. (1954). "Optical Principles of the Diffraction of X-Rays." 2.


97. Sizemore, C., Buchner, E., Rygus, T., Witke, C., Götz, F. and Hillen, W. (1991). "Organization, promoter analysis and transcriptional regulation of the Staphylococcus xylosus xylose utilization operon." Molecular Genetics and Genomics. 227(3): 377-384.


98. Otwinowski, Z. and Minor, W. (1997). "Processing of X-ray diffraction data collected in oscillation mode." Methods in Enzymology 276: 307-326.


99. "PROCHECK: a program to check the stereochemical quality of protein structures." J. Appl. Crystallog. 26: 283-291.


100. Blundell, T. L. and Johnson, L. N. (1976). Protein Crystallography.


101. Gjertsen, B. T. and Døskeland, S. O. (1995). "Protein phosphorylation in apoptosis." Biochimica et Biophysica Acta (BBA) -Molecular Cell Research 1269(2): 187- 199.


102. Kristo, P., Saarelainen, R., Fagerström, R., Aho, S. and Korhola, M. (1996). "Protein Purification, and Cloning and Characterization of the cDNA and Gene for Xylose Isomerase of Barley." European Journal of Biochemistry 237(1): 240- 246.


103. Romier, C., Ficner, R., Reuter, K. and Suck, D. (1996). "Purification, crystallization, and preliminary x-ray diffraction studies of tRNA-guanine transglycosylase from Zymomonas mobilis." Proteins 24(4): 516-519.


104. Brown, D. and Superti-Furga, G. (2003). "Rediscovering the sweet spot in drug discovery." Drug Discovery Today 8(23): 1067-1077.


105. Huggenvik, J. I., Collard, M. W., Stofko, R. E., Seasholtz, A. F. and Uhler, M. D. (1991). "Regulation of the Human Enkephalin Promoter by Two Isoforms of the Catalytic Subunit of Cyclic Adenosine 3',5'-Monophosphate-Dependent Protein Kinase." Mol Endocrinol 5(7): 921-930.


106. Hendlich, M., Bergner, A., Günther, J. and Klebe, G. (2003). "Relibase: Design and Development of a Database for Comprehensive Analysis of Protein-Ligand Interactions." Journal of Molecular Biology 326(2): 607-620.


107. Wang, B.-C., Wyckoff, H. W., Hirs, C. H. W. and Timasheff, S., N. (1985). Resolution of phase ambiguity in macromolecular crystallography. Methods in Enzymology, Academic Press. Volume 115: 90-112.


108. Allen, K. N., Lavie, A., Glasfeld, A., Tanada, T. N., Gerrity, D. P., Carlson, S. C., Farber, G. K., Petsko, G. A. and Ringe, D. (1994). "Role of the Divalent Metal Ion in Sugar Binding, Ring Opening, and Isomerization by D-Xylose Isomerase: Replacement of a Catalytic Metal by an Amino Acid." Biochemistry 33(6): 1488-1494.


109. Pichová, I., Pavlíková, L., Dostá, J. í., l, Dolejsi, E., Hrusková-Heidingsfeldová, O., Weber, J., Ruml, T. and Soucek, M. (2001). "Secreted aspartic proteases of Candida albicans, Candida tropicalis, Candida parapsilosis and Candida lusitaniae." European Journal of Biochemistry 268(9): 2669-2677.


110. "SHELXL: high-resolution refinment." Methods in Enzymology: 319-343.


111. Quillin, M. L., Breyer, W. A., Griswold, I. J. and Matthews, B. W. (2000). "Size versus polarizability in protein-ligand interactions: binding of noble gases within engineered cavities in phage T4 lysozyme." Journal of Molecular Biology 302(4): 955-977.


112. Davies, S. P., Reddy, H., Caivano, M. and Cohen, P. (2000). "Specificity and mechanism of action of some commonly used protein kinase inhibitors." Journal of Biological Chemistry 351(1): 95-105. regulatory network of the virulence of Shigella flexneri: the expression of the virF gene." Molecular Microbiology 35(4): 924-935.


113. Badger, J., Sauder, J. M., Adams, J. M., Antonysamy, S., Bain, K., Bergseid, M. G., Buchanan, S. G., Buchanan, M. D., Batiyenko, Y., Christopher, J. A., Emtage, S., Eroshkina, A., Feil, I., Furlong, E. B., Gajiwala, K. S., Gao, X., He, D., Hendle, J., Huber, A., Hoda, K., Kearins, P., Kissinger, C., Laubert, B., Lewis, H. A., Lin, J., Loomis, K., Lorimer, D., Louie, G., Maletic, M., Marsh, C. D., Miller, I., Molinari, J., Muller-Dieckmann, H. J., Newman, J. M., Noland, B. W., Pagarigan, B., Park, F., Peat, T. S., Post, K. W., Radojicic, S., Ramos, A., Romero, R., Rutter, M. E., Sanderson, W. E., Schwinn, K. D., Tresser, J., Winhoven, J., Wright, T. A., Wu, L., Xu, J. and Harris, T. J. R. (2005). "Structural analysis of a set of proteins resulting from a bacterial genomics project." Proteins: Structure, Function, and Bioinformatics 60(4): 787-796.


114. Stengl, B. (2006). Structural and Functional Studies of tRNA-Guanine Transglycosylase: A putative Drug Target of Shigellosis Therapy. Ph D Thesis, Philipps-University Marburg.


115. Holland, D. R., Tronrud, D. E., Pley, H. W., Flaherty, K. M., Stark, W., Jansonius, J. N., McKay, D. B. and Matthews, B. W. (1992). "Structural comparison suggests that thermolysin and related neutral proteases undergo hinge-bending motion during catalysis." Biochemistry 31(46): 11310-11316.


116. "Structural evidence for gene duplication in the evolution of the acid proteases." Nature 271: 618-621.


117. bis 05/2006 Forschungsaufenthalt zum Thema: " Structural studies on proteins involved in the mycobactin biosynthese pathway " der School of Biological Science im Arbeitkreis von Prof. E.N. Baker an der Auckland University, Neuseeland, im Rahmen der einjährigen praktischen pharmazeutischen Ausbildung 04/2001 bis 09/2005 Pharmaziestudium an der Philipps Universität Marburg LEHRTÄTIGKEITEN Seit 01/2007


118. Carr, R. and Jhoti, H. (2002). "Structure-based screening of low-affinity compounds." Drug Discovery Today 7(9): 522-527.


119. Gaikwad, S., Rao, M. and Deshpande, V. (1993). "Structure-function relationship of glucose/xylose isomerase from Streptomyces: Evidence for the occurrence of inactive dimer." Enzyme and Microbial Technology 15(2): 155-157.


120. Blum, A., Böttcher, J., Heine, A., Klebe, G. and Diederich, W. E. (2008). "Structure- Guided Design of C2-Symmetric HIV-1 Protease Inhibitors Based on a Pyrrolidine Scaffold." Journal of Medicinal Chemistry 51(7): 2078-2087.


121. Richard, S. B., Bowman, M. E., Kwiatkowski, W., Kang, I., Chow, C., Lillo, A. M., Cane, D. E. and Noel, J. P. (2001). "Structure of 4-diphosphocytidyl-2-C- methylerythritol synthetase involved in mevalonate-independent isoprenoid biosynthesis." Nature Structural Molecular Biolology 8(7): 641-648.


122. Knighton, D. R., Zheng, J. H., Ten Eyck, L. F., Xuong, N. H., Taylor, S. S. and Sowadski, J. M. (1991). "Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase." Science 253(5018): 414-420.


123. Abad-Zapatero, C., Goldman, R., Muchmore, S., W. , Hutchins, C., Stewart, K., Navaza, J., Payne, C., D. and Ray, T., L. (1996). "Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: Implications for the design of antifungal agents." Protein Science 5(4): 640-652.


124. Hendrickson, W. A. and Teeter, M. M. (1981). "Structure of the hydrophobic protein crambin determined directly from the anomalous scattering of sulphur." Nature 290(5802): 107-113.


125. Kryger, G., Harel, M., Giles, K., Toker, L., Velan, B., Lazar, A., Kronman, C., Barak, D., Ariel, N., Shafferman, A., Silman, I. and Sussman, J. L. (2000). "Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II." Acta Crystallographica Section D 56(11): 1385-1394.


126. Blum, A. (2007). Strukturbasiertes Design und Synthese von Pyrrolidinen als Inhibitoren der HIV-1-Protease. Ph D Thesis, Philipps-University Marburg.


127. Verdonk, M. L., Cole, J. C. and Taylor, R. (1999). "SuperStar: A Knowledge-based Approach for Identifying Interaction Sites in Proteins." Journal of Molecular Biology 289(4): 1093-1108.


128. Böttcher, J., Blum, A., Dörr, S., Heine, A., Diederich, W., E. and Klebe, G. (2008). "Targeting the Open-Flap Conformation of HIV-1 Protease with Pyrrolidine- Based Inhibitors." ChemMedChem 3(9): 1337-1344.


129. Staib, P., Lermann, U., Blaß-Warmuth, J., Degel, B., Wurzner, R., Monod, M., Schirmeister, T. and Morschhauser, J. (2008). "Tetracycline-Inducible Expression of Individual Secreted Aspartic Proteases in Candida albicans Allows Isoenzyme-Specific Inhibitor Screening." Antimicrob. Agents Chemother. 52(1): 146-156.


130. Ritschel, T. (2009). TGT a Drug Target to Study pKa Shifts, Residual Solvation & Protein -Protein Interface Formation. Ph D Thesis, Philipps-University Marburg.


131. Lichtenthaler, H. K. (1999). "The 1-Deoxy-D-Xylulose-5-Phosphate Pathway of Isoprenoid Biosynthesis in Plants." Annual Review of Plant Physiology and Plant Molecular Biology 50(1): 47-65.


132. Holden, H. M. and Matthews, B. W. (1988). "The binding of L-valyl-L-tryptophan to crystalline thermolysin illustrates the mode of interaction of a product of peptide hydrolysis." Journal of Biological Chemistry 263(7): 3256-3260.


133. Taylor, P. and Radic, Z. (1994). "The Cholinesterases: From Genes to Proteins." Annual Review of Pharmacology and Toxicology 34(1): 281-320.


134. Eisenreich, W., Schwarz, M., Cartayrade, A., Arigoni, D., Zenk, M. H. and Bacher, A. (1998). "The deoxyxylulose phosphate pathway of terpenoid biosynthesis in plants and microorganisms." Chemistry & Biology 5(9): R221-R233.


135. Patchett, A., A. and Cordes, E., H. (2006). The Design and Properties of N- Carboxyalkyldipeptide Inhibitors of Angiotensin-Converting Enzyme. Advances in Enzymology and Related Areas of Molecular Biology. Alton, M.: 1-84.


136. Rohmer, M. (1999). "The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants." Natural Product Reports 16: 565-574.


137. Bokhoven, C., Schoone, J. C. and Bijvoet, J. M. (1951). "The Fourier synthesis of the crystal structure of strychnine sulphate pentahydrate." Acta Crystallographica 4(3): 275-280.


138. Smith, A., W. , Chahal, B. and French, G., L. (1994). "The human gastric pathogen Helicobacter pylori has a gene encoding an enzyme first classified as a mucinase in Vibrio cholerae." Molecular Microbiology 13(1): 153-160.


139. Ollis, D. L., Cheah, E., Cygler, M., Dijkstra, B., Frolow, F., Franken, S. M., Harel, M., Remington, S. J., Silman, I., Schrag, J., Sussman, J. L., Verschueren, K. H. G. and Goldman, A. (1992). "The α/β -hydrolase fold." Protein Engineering. 5(3): 197-211.


140. Rossmann, M. (1961). "The position of anomalous scatterers in protein crystals." Acta Crystallographica 14(4): 383-388.


141. Bernstein, F. C., Koetzle, T. F., Williams, G. J. B., Meyer, J. E. F., Brice, M. D., Rodgers, J. R., Kennard, O., Shimanouchi, T. and Tasumi, M. (1977). "The protein data bank: A computer-based archival file for macromolecular structures." Journal of Molecular Biology 112(3): 535-542.


142. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002). "The Protein Kinase Complement of the Human Genome." Science 298(5600): 1912- 1934.


143. Davies, D. R. (1990). "The Structure and Function of the Aspartic Proteinases." Annual Review of Biophysics and Biophysical Chemistry 19(1): 189-215.


144. Cooper, J., Foundling, S., Hemmings, A., Blundell, T., Jones, M., D. , Hallett, A. and Szelke, M. (1987). "The structure of a synthetic pepsin inhibitor complexed with endothiapepsin." European Journal of Biochemistry 169(1): 215-221.


145. Stark, W., Pauptit, R., A. , Wilson, K., S. and Jansonius, J., N. (1992). "The structure of neutral protease from Bacillus cereus at 0.2 nm resolution." European Journal of Biochemistry 207(2): 781-791.


146. Matthews, B. W. (1972). "The γ-Turn. Evidence for a New Folded Conformation in Proteins." Macromolecules 5(6): 818-819.


147. Niesen, F. H., Berglund, H. and Vedadi, M. (2007). "The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability." Nature Protocols 2(9): 2212-2221.


148. Smith, F. D., Langeberg, L. K. and Scott, J. D. (2006). "The where's and when's of kinase anchoring." Trends in Biochemical Sciences 31(6): 316-323.


149. Meaden, P. G., Aduse-Opoku, J., Reizer, J., Reizer, A., Lanceman, Y. A., Martin, M. F. and Mitchell, W. J. (1994). "The xylose isomerase-encoding gene (xy1A) of Clostridium thermosaccharolyticum: cloning, sequencing and phylogeny of xy1A enzymes." Gene 141(1): 97-101.


150. Sussman, J. L., Harel, M. and Silman, I. (1993). "Three-dimensional structure of acetylcholinesterase and of its complexes with anticholinesterase drugs." Chemico-Biological Interactions 87(1-3): 187-197.


151. Herrmann, G., Selmer, T., Jessen, H., J. , Gokarn, R., R. , Selifonova, O., Gort , S., J. and Buckel, W. (2005). "Two beta-alanyl-CoA:ammonia lyases in Clostridium propionicum." FEBS Journal 272(3): 813-821.


152. Gonzalez, A., Pedelacq, J. D., Sola, M., Gomis-Ruth, F. X., Coll, M., Samama, J. P. and Benini, S. (1999). "Two-wavelength MAD phasing: in search of the optimal choice of wavelengths." Acta Crystallographica Section D 55(8): 1449-1458.


153. Cummings, M. D., Farnum, M. A. and Nelen, M. I. (2006). "Universal Screening Methods and Applications of ThermoFluor®." Journal of Biomolecular Screening 11(7): 854-863.


154. Vitali, J., Robbins, A. H., Almo, S. C. and Tilton, R. F. (1991). "Using xenon as a heavy atom for determining phases in sperm whale metmyoglobin." Journal of Applied Crystallography 24(5): 931-935.


155. Booth, B. A., Boesman-Finkelstein, M. and Finkelstein, R. A. (1983). "Vibrio cholerae soluble hemagglutinin/protease is a metalloenzyme." Infectection and Immunity 42(2): 639-644.


156. Walters, W. P., Stahl, M. T. and Murcko, M. A. (1998). "Virtual screening -an overview." Drug Discovery Today 3(4): 160-178.


157. Brenk, R. (2002). Virtuelles Screening, strukturbasiertes Design und Kristallstrukturanalyse von Inhibitoren der tRNA-Guanin Transglykosylase, ein Target der Bakterienruhr. Ph D Thesis, Philipps-University Marburg.


158. Blundell, T. L., Jenkins, J. A., Sewell, B. T., Pearl, L. H., Cooper, J. B., Tickle, I. J., Veerapandian, B. and Wood, S. P. (1990). "X-ray analyses of aspartic proteinases : The three-dimensional structure at 2.1 Å resolution of endothiapepsin." Journal of Molecular Biology 211(4): 919-941.


159. Carrell, H. L., Rubin, B. H., Hurley, T. J. and Glusker, J. P. (1984). "X-ray crystal structure of D-xylose isomerase at 4-A resolution." Journal of Biological Chemistry 259(5): 3230-3236.


160. Lönn, A., Träff-Bjerre, K. L., Cordero Otero, R. R., van Zyl, W. H. and Hahn-Hägerdal, B. (2003). "Xylose isomerase activity influences xylose fermentation with recombinant Saccharomyces cerevisiae strains expressing mutated xylA from Thermus thermophilus." Enzyme and Microbial Technology 32(5): 567-573.


161. "Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats." Journal of Hypertension 23(2): 417-426.


162. Emsley, P. and Cowtan, K. (2004). "Coot: model-building tools for molecular graphics." Acta Crystallographica Section D 60: 2126.


163. Varsani, L., Cui, T., Rangarajan, M., Hartley, B. S., Goldberg, J., Collyer, C. and Blow, D. M. (1993). "Arthrobacter D-xylose isomerase: protein-engineered subunit interfaces." Biochemical Journal 291(2): 575-583.


164. Rangarajan, M., Asboth, B. and Hartley, B. S. (1992). "Stability of Arthrobacter D- xylose isomerase to denaturants and heat." Biochem J. 285(3): 889-898.


165. Rohmer, M., Knani, M., Simonin, P., Sutter, B. and Sahm, H. (1993). "Isoprenoid biosynthesis in bacteria: a novel pathway for the early steps leading to isopentenyl diphosphate." Biochem J. 295: 517-524.


166. Eisenreich, W., Bacher, A., Arigoni, D. and Rohdich, F. (2004). "Biosynthesis of isoprenoids via the non-mevalonate pathway." Cellular and Molecular Life Sciences 61(12): 1401-1426.


167. Thayer, M. M., Flaherty, K. M. and McKay, D. B. (1991). "Three-dimensional structure of the elastase of Pseudomonas aeruginosa at 1.5-A resolution." Journal of Biological Chemistry 266(5): 2864-2871.


168. Lawrence, J. H., Loomis, W. F., Tobias, C. A. and Turpin, F. H. (1946). "Preliminary observations on the narcotic effect of xenon with a review of values for solubilities of gases in water and oils." Journal of Physiology 195: 197-204.


169. Liu, S. Y., Wiegel, J. and Gherardini, F. C. (1996). "Purification and cloning of a thermostable xylose (glucose) isomerase with an acidic pH optimum from Thermoanaerobacterium strain JW/SL-YS 489." J. Bacteriol. 178(20): 5938- 5945.


170. Machius, M., Henry, L., Palnitkar, M. and Deisenhofer, J. (1999). "Crystal structure of the DNA nucleotide excision repair enzyme UvrB from Thermus thermophilus." Proceedings of the National Academy of Sciences of the United States of America 96(21): 11717-11722.


171. Naglik, J. R., Challacombe, S. J. and Hube, B. (2003). "Candida albicans Secreted Aspartyl Proteinases in Virulence and Pathogenesis." Microbiology and Molecular Biology Reviews. 67(3): 400-428.


172. White, T. C., Miyasaki, S. H. and Agabian, N. (1993). "Three distinct secreted aspartyl proteinases in Candida albicans." The Journal of Bacteriology. 175(19): 6126- 6133.


173. Harel, M., Kryger, G., Rosenberry, T., L. , Mallender, W., D. , Lewis, T., Fletcher, R., J. , Guss, J. M., Silman, I. and Sussman, J., L. (2000). "Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors." Protein Science 9(6): 1063-1072.


174. "Cloning and sequencing of the xylose isomerase and xylulose kinase genes of Escherichia coli." Appl. Environ. Microbiol. 47(1): 15-21.


175. Chen, W. P., Anderson, A. W. and Han, Y. W. (1979). "Extraction of glucose isomerase from Streptomyces flavogriseus." Applied and Environmental Microbiology. 37(4): 785-787.


176. Rodgers, D. W. (1994). "Cryocrystallography." Structure 2(12): 1135-1140.


177. Park, J.-H. and Batt, C. A. (2004). "Restoration of a Defective Lactococcus lactis Xylose Isomerase." Applied and Environmental Microbiology. 70(7): 4318- 4325.


178. Ripoll, D. R., Faerman, C. H., Axelsen, P. H., Silman, I. and Sussman, J. L. (1993). "An electrostatic mechanism for substrate guidance down the aromatic gorge of acetylcholinesterase." PNAS 90(11): 5128-5132.


179. Hendrickson, W. A., Horton, J. R. and LeMaster, D. M. (1990). "Selenomethionyl proteins produced for analysis by multiwavelength anomalous diffraction (MAD): a vehicle for direct determination of three-dimensional structure." EMBO J. 9(5): 1665-1672.


180. Erlandson, K. A., Park, J.-H., Wissam, El, K., Kao, H.-H., Basaran, P., Brydges, S. and Batt, C. A. (2000). "Dissolution of Xylose Metabolism in Lactococcus lactis." Applied and Environmental Microbiology. 66(9): 3974-3980.


181. Holmes, M. A. and Matthews, B. W. (1982). "Structure of thermolysin refined at 1.6 Å resolution." Journal of Molecular Biology 160(4): 623-639.


182. Nolte, H.-J., Rosenberry, T. L. and Neumann, E. (1980). "Effective charge on acetylcholinesterase active sites determined from the ionic strength dependence of association rate constants with cationic ligands." Biochemistry 19(16): 3705- 3711.