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Titel Constitutive Activity of the Human Histamine H4 Receptor: Molecular Modelling, Binding and Functional Studies on Wild-Type and Mutant H4R Orthologs

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Titel Constitutive Activity of the Human Histamine H4 Receptor: Molecular Modelling, Binding and Functional Studies on Wild-Type and Mutant H4R Orthologs Titel Constitutive activity of the human histamine H4 receptor: Molecular modelling, binding and functional studies on wild-type and mutant H4R orthologs Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) an der Fakultät für Chemie und Pharmazie der Universität Regensburg vorgelegt von David Wifling aus Bad Griesbach 2015 Die vorliegende Arbeit entstand in der Zeit von Mai 2011 bis Dezember 2014 unter der Anleitung von Herrn Prof. Dr. A. Buschauer und Herrn Prof. Dr. S. Dove am Institut für Pharmazie der Fakultät für Chemie und Pharmazie der Universität Regensburg. Das Promotionsgesuch wurde eingereicht im Februar 2015 Tag der mündlichen Prüfung: 13. März 2015 Prüfungsausschuss: Prof. Dr. A. Slenczka (Vorsitzender) Prof. Dr. A. Buschauer (Erstgutachter) Prof. Dr. S. Dove (Zweitgutachter) Prof. Dr. S. Elz (Drittprüfer) Widmung Für meine liebste Maria „Phantasie ist wichtiger als Wissen, denn Wissen ist begrenzt.“ Albert Einstein, 1879-1955 Danksagungen An dieser Stelle möchte ich mich bedanken bei: Herrn Prof. Dr. A. Buschauer, dass ich an einem so interessanten Thema arbeiten durfte, sowie dass ich meine in silico erzeugten Hypothesen experimentell mittels Herstellung von Rezeptormutanten überprüfen durfte. Ganz herzlichen Dank auch dafür, dass ich sehr frei war in der Projektplanung, für die sehr guten Diskussionen sowie die konstruktive Kritik bei der Durchsicht dieser Arbeit und der Publikationen. Herrn Prof. Dr. S. Dove für seine konstruktive Kritik zu diversen Modelling-Themen, bei der Interpretation der Ergebnisse sowie bei der Durchsicht dieser Arbeit und der Publikationen. Herrn Prof. Dr. R. Seifert (Institut für Pharmakologie, Medizinische Hochschule Hannover) für seine zielführenden Beiträge unter anderem zu Western Blots und diversen Assays, sowie bei der Durchsicht der im Br. J. Pharmacol. veröffentlichten Publikation. Herrn Prof. Dr. G. Bernhardt insbesondere für die Unterstützung bei der Bestimmung der Rezeptor- und G-Proteinexpressionslevel verschiedener Rezeptor-Konstrukte, sowie für die Durchsicht der Publikationen. Frau PD Dr. A. Strasser und Herrn Prof. Dr. S. Dove für die Bereitstellung des auf der Kristallstruktur des inaktiven hH1R (PDB ID: 3RZE) basierenden hH4R Homologiemodells. Herrn Prof. Dr. S. Elz für die Ermöglichung, ein Tutorium für die Studentinnen und Studenten im ersten Semester Pharmazie zu halten, sowie für die Bereitschaft als Drittprüfer an der mündlichen Prüfung teilzunehmen. Herrn Prof. Dr. A. Slenczka für die Bereitschaft, dem Prüfungsausschuss vorzustehen. Frau K. Löffel für die gute Zusammenarbeit sowie die zahlreichen fachlichen Diskussionen während der Anfertigung ihrer Diplomarbeit. Insbesondere danke ich für die Bereitstellung der in [3H]Histamin Sättigungs-, Bindungs- und [35S]GTPγS-Experimenten ermittelten Daten zu den von ihr generierten hH4R-F169V und mH4R-V171F Mutanten. Herrn Dr. U. Nordemann für die Testung zweier Rezeptormutanten in der [3H]Histamin Sättigung sowie die Durchführung von [3H]Histamin Kompetitions-Bindungs Experimenten mit dem hH4R Wildtyp und fünf hH4R Mutanten. Ferner vielen Dank für die fachlichen Diskussionen. Frau Dr. I. Brunskole und Frau K. Ladova für die Bereitstellung der Baculoviren für die hH4R-R341S und hH4R-R341E Mutanten. Herrn Dr. P. Baumeister für die Bereitstellung von Daten zum hH4R bezüglich eines [3H]Histamin Sättigungsexperimentes sowie mehrerer [3H]Histamin Kompetitions-Bindungs Experimente mit Histamin, JNJ7777120 und VUF8430 als Kompetitor. Herrn Dr. T. Holzammer für die Einführung in das Molecular Modelling sowie für die vielen Gespräche zu den Themen Molecular Modelling, Mutagenese und zu pharmakologischen Fragestellungen. Herrn Dr. M. Keller für die vielen Diskussionen unter anderem zu pharmakologischen Parametern und deren Auswertung bzw. Interpretation. meinen derzeitigen und ehemaligen Bürokollegen Herrn Dr. P. Baumeister, Frau Dr. M. Ertel, Herrn Dr. T. Holzammer, Frau Dr. A. Kaczor und Herrn Dr. M. Keller für die angenehme Atmosphäre und die vielen fachlichen Diskussionen. Herrn Dr. P. Igel für die Bereitstellung der H4R Agonisten UR-PI294 und UR-PI376, Frau Dr. S. Gobleder für die Bereitstellung des H4R Agonisten Isoloxapin sowie Herrn Dr. P. Baumeister für die Bestellung von [35S]GTPγS und [3H]Histamin. Frau M. Beer-Krön sowie Frau G. Wilberg für die Kultivierung der Sf9 Zellen sowie Frau M. Beer-Krön und Frau D. Fritsch für die Durchführung einiger Assays. Herrn P. Richthammer für die tatkräftige Unterstützung bei technischen Problemen. Frau U. Hasselmann, Frau S. Heinrich und Frau K. Reindl für ihre freundliche Hilfe bei vielen organisatorischen Fragen. dem Graduiertenkolleg GRK 760 der DFG für die finanzielle Unterstützung sowie die wissenschaftliche Ausbildung. allen Kollegen und studentischen Hilfskräften für die Vorbereitung und Durchführung zahlreicher Praktika. Besonders danke ich meinen Eltern Ingrid und Walter, meinen Geschwistern Judith, Raphael und Manuel für ihre Unterstützung jeglicher Art, für ihr stets offenes Ohr sowie die schöne Zeit zu Hause. Mein besonderer Dank gilt meiner lieben Freundin Maria für die Unterstützung während der Promotion, für die schönen Unternehmungen, und besonders für die Liebe, die sie mir geschenkt hat. I Contents 1 Introduction ......................................................................... 1 1.1 G-protein coupled receptors ................................................................... 1 1.1.1 GPCR classes ..................................................................................................... 2 1.1.2 Structure of G-protein coupled receptors ............................................................. 3 1.1.3 Function of G-protein coupled receptors.............................................................. 4 1.1.4 Models of ligand binding and G-protein coupling ................................................. 5 1.1.4.1 Classical model ................................................................................................................... 5 1.1.4.2 Operational model ............................................................................................................... 5 1.1.4.3 Ternary complex models ..................................................................................................... 6 1.1.5 Constitutive activity of GPCRs ............................................................................. 7 1.1.6 Signal transduction .............................................................................................. 8 1.1.6.1 Structure of G-proteins and G-protein cycle ....................................................................... 8 1.1.6.2 Functions of different G-protein subtypes ......................................................................... 10 1.1.6.3 β-arrestin-mediated GPCR internalization and signalling ................................................. 11 1.2 Histamine and histamine receptors ..................................................... 13 1.2.1 Historical perspective of histamine .....................................................................13 1.2.2 Histamine: occurrence and metabolism ..............................................................14 1.2.3 Histamine receptor subtypes and ligands ...........................................................15 1.2.3.1 Homologies between the four histamine receptor subtypes ............................................. 15 1.2.3.2 Key amino acids of the four histamine receptor subtypes ................................................ 16 1.2.3.3 Selectivity profile of histamine receptor ligands ................................................................ 17 1.2.3.4 H1 receptor ........................................................................................................................ 18 1.2.3.5 H2 receptor ........................................................................................................................ 20 1.2.3.6 H3 receptor ........................................................................................................................ 21 1.2.3.7 H4 receptor ........................................................................................................................ 22 1.3 Species differences ............................................................................... 26 1.3.1 Homologies between H4R species variants ........................................................26 1.3.2 Key amino acids of the H4R species orthologs ...................................................26 1.3.3 Pharmacological characteristics of H4R species orthologs .................................28 1.4 References ............................................................................................. 31 2 Scope and Objectives .......................................................... 47 2.1 References ............................................................................................. 49 3 Computational Chemistry .................................................... 51 3.1 Summary ................................................................................................ 51 3.2 Introduction ............................................................................................ 52 3.3 Methods .................................................................................................. 53 3.3.1 Available GPCR crystal structures ......................................................................53 3.3.2 H3R/H4R homology models
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