Publikationsserver der Universitätsbibliothek Marburg

Titel:Kristallstrukturen mit kleinen Sondenmolekülen: Ausleuchten von Bindetaschen, Startpunkt für ein Fragment-basiertes Wirkstoffdesign und Erhalten von Phaseninformationen zur Strukturlösung
Autor:Behnen, Jürgen
Weitere Beteiligte: Klebe, Gerhard (Prof.)
Veröffentlicht:2011
URI:https://archiv.ub.uni-marburg.de/diss/z2011/0076
URN: urn:nbn:de:hebis:04-z2011-00767
DOI: https://doi.org/10.17192/z2011.0076
DDC:500 Naturwissenschaften
Titel (trans.):X-ray Crystallography of Proteins with Fragments: Experimental Active Site Mapping as a Starting Point in Fragment-based Lead Discovery and 3D-Structure Determination via SAD-Phasing
Publikationsdatum:2011-03-17
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
FBLD, Fragmentbasierte Leitstrukturentwicklung, IspD, SAD-Phasing, Proteinkristallographie, X-ray crystallography, Xenon, SAD-Phasing, IspD

Zusammenfassung:
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 neuer Leitstrukturen im Kampf gegen Malaria und Tuberkulose. Der Schwerpunkt dieser Arbeit befasste sich mit der Suche nach Sondenmolekülen, die sich eignen, um Bindetaschen verschiedne Proteinsysteme experimentell über Röntgenstrukturanalyse auszuleuchten. Diese experimentell charakterisierten Bindungsstellen in Proteinbindetaschen werden auch als HotSpots bezeichnet. Sie stellen die Grundlage dar, um einen proteinbasierten Pharmakophore abzuleiten. Über Soaking und Co-Kristallisation wurde versucht, sehr kleine, hydrophile Moleküle in die Bindetasche der Zielproteine hinein diffundieren zu lassen. Bis zum heutigen Zeitpunkt sind 25 Fragmente und Gase unterschiedlicher Größe und Eigenschaften an dem Proteinsystem TLN mit Hilfe der Röntgenstrukturanalyse vorab durchgemustert worden. Es konnten das Bindungsverhalten von Anilin, 3-Bromphenol, 2-Bromessigsäure, 1,2-Propandiol, Harnstoff, N-Methylharnstoff und N2O im aktiven Zentrum von TLN charakterisiert werden. Diese an TLN erfolgreich etablierten Sondenmoleküle wurden auf andere Proteinsysteme übertragen. Im aktiven Zentrum von PKA konnten jeweils zwei Moleküle Phenol und N-Methylharnstoff sowie in der Bindetasche von DXI und IspD jeweils ein 1,2-Propandiolmolekül charakterisiert werden. Diese experimentell ermittelten HotSpots wurden im Anschluss mit theoretisch berechneten HotSpots unter Verwendung des Programms DrugScoreHotSpot verglichen. Es konnte in diesem Ansatz gezeigt werden, dass die theoretisch berechneten Vorhersagen von HotSpots in Proteinbindetaschen gut mit den experimentell gewonnenen Erkenntnissen übereinstimmten. Dadurch stellt die Kombination beider Ansätze eine hervorragende Möglichkeit dar, proteinbasierte Pharmakophore zu erstellen und mit Hilfe dieser neue Arzneistoffe zu entwickeln. In Kooperation mit dem Arbeitskreis von Prof. Joel L. Sussman in Rehovot, Israel, gelang es, durch Inkorporation von Xenon in Proteinkristallen von Thermolysin und TcAcetylcholinesterase die 3D-Struktur der jeweiligen Xenonproteinkomplexe über SAD (Single Anomalous Dispersion) an einer hauseigenen Röntgenquelle zu bestimmen. Zusätzlich wurden auch noch die Enzyme Endothiapepsin, TGT und Sap2 mit Xenon derivatisiert. Allerdings war es dabei nur möglich, die Struktur von Endothiapepsin über SAD mit in house gesammelten Daten zu bestimmten. Nichts desto trotz konnte an Hand der Modellsystemen Thermolysin, TcAcetylcholinesterase und Endothiapepsin gezeigt werden, daß die Strukturbestimmung von Proteinen unterschiedlicher Enzymklassen, Größe und Symmetrie mit Hilfe des Edelgases Xenon als Schweratomderivat durch die SAD-Methode anhand von in house gesammelten Daten eine einfache, toxikologisch unbedenkliche und leicht durchzuführende Alternative zu herkömmlichen Methoden, wie z.B. Quecksilber- oder Selenmethioninderivaten, darstellt. Als drittes und letztes Thema der Arbeit wurde am Beispiel des Enzyms 4-Diphosphocytidyl-2C-methyl-D-erythritol-4-phosphat-synthase (IspD) versucht, eine neue Leitstruktur gegen Malaria und Tuberkulose zu entwickeln. Basis war hier eine Kristallstruktur mit dem Fragment 1,2-Propandiol in der Bindetasche. Über einen Thermofluoro-Assay und mit Hilfe der Röntgenstrukturanalyse wurde versucht, ein zum Cytidin basenanaloges Molekül zu finden, welches in die Basentasche von IspD binden sollte. Das Ziel dabei war es, beide Fragmente passend miteinander zu verbinden, um so eine neue hochpotente Leitstruktur gegen Malaria und Tuberkulose zu erhalten. Obwohl die Apo-Struktur von IspD bekannt ist, war es nötig neue, reproduzierbaren und für Diffraktionsexperimente tauglichen IspD-Kristallen zu finden. Hierfür wurden weit mehr als 1000 verschieden Kristallisationsbedingungen getestet. In einer Feinabstimmung der anfänglich gefunden Bedingungen ließen sich reproduzierbare und ausreichend streuende Kristalle erhalten. Das Streuverhalten von in house vermessenen IspD-Kristallen konnte von einer anfänglichen Auflösung von 4,0 Å bis hin zu 2,34 Å verbessert werden. Zusätzlich wurde das bestehende Expressions- und Reinigungsprotokoll bezüglich der Ausbeute an IspD weiter verbessert. Die Ausbeute an IspD konnte von 135 mg auf 208 mg IspD pro 4 l Ansatz gesteigert werden. Durch einen Thermofluoro-Assay wurden bisher 24 entweder gekaufte oder auch hauseigene Substanzen durchgemustert, um eine Vorauswahl an Fragmenten für die Röntgenstrukturanalyse zu finden. Bei diesen Messungen kristallisierten sich die 6 Liganden mit einer Schmelzpunktverschiebung von 2° – 7,5° C als sehr vielversprechend heraus. Es ist außerdem gelungen die erste substratunabhängige IspD-Komplexstruktur in der PDB zu deponieren.

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