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Etude Structurale Des Cassures D'hélices Et Etude structurale des cassures d’hélices et son application à la modélisation des récepteurs couplés aux protéines G (RCPG) Julie Devillé To cite this version: Julie Devillé. Etude structurale des cassures d’hélices et son application à la modélisation des ré- cepteurs couplés aux protéines G (RCPG). Modélisation et simulation. Université d’Angers, 2007. Français. tel-00346950 HAL Id: tel-00346950 https://tel.archives-ouvertes.fr/tel-00346950 Submitted on 12 Dec 2008 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE D’ANGERS Année : 2007 N° d’ordre : 889 ETUDE STRUCTURALE DES CASSURES D’HELICES ET SON APPLICATION A LA MODELISATION DES RECEPTEURS COUPLES AUX PROTEINES G (RCPG) THESE DE DOCTORAT Spécialité : Bioinformatique ECOLE DOCTORALE D’ANGERS Présentée et soutenue publiquement Le : 19/12/2007 à : Angers par Julie Devillé Devant le jury ci-dessous : Dr J.F. Gibrat (rapporteur), DR, INRA, Jouy-en-Josas Dr I. Milazzo (rapporteur), MCU, UMR CNRS 6014, Rouen Pr C. Delamarche (examinateur), PU, UMR CNRS 6026, Rennes Dr C. Legros (examinateur), MCU, UPRES EA 2647, Angers Dr M. Chabbert (examinateur), CR, UMR CNRS 6214- INSERM 771, Angers Directeur de Thèse : Dr M. Chabbert, CR, UMR CNRS 6214 - INSERM 771, Angers Laboratoire : UMR CNRS 6214 - INSERM 771, Laboratoire de Biologie Neurovasculaire Intégrée Rue Haute de Reculee 49045 ANGERS CEDEX 01 1 TABLE DES MATIERES INTRODUCTION GENERALE..................................................................................................7 1 LES RECEPTEURS COUPLES AUX PROTEINES G....................................................11 1.1 La famille des récepteurs couplés aux protéines G ....................................................12 1.2 Classification des RCPG............................................................................................13 1.2.1 Diversité des récepteurs couplés aux protéines G :............................................13 1.2.2 Classification historique par ligands de GPCRdb ..............................................13 1.2.3 Le système de classification GRAFS.................................................................15 1.2.3.1 Les cinq familles de la classification GRAFS................................................17 1.2.3.2 La famille de la rhodopsine............................................................................18 1.2.4 Classification par Analyse par Composante Principale (ACP)..........................21 1.3 Nos récepteurs d’intérêt..............................................................................................21 1.3.1 Les récepteurs de l’angiotensine : AT1 et AT2..................................................23 1.3.1.1 Fonctionnement..............................................................................................23 1.3.1.2 Les récepteurs AT1 et AT2 ...........................................................................23 1.3.2 Les autres récepteurs du groupe 1......................................................................25 1.3.2.1 Les autres récepteurs de peptides vasoactifs ..................................................25 1.3.2.2 Les récepteurs des chimiokines......................................................................26 1.3.2.3 Les récepteurs opioïdes/somatostatines..........................................................26 1.3.2.4 Les récepteurs MCH.......................................................................................26 1.3.2.5 Les récepteurs purinergiques..........................................................................27 1.4 Structure des RCPG de classe A ................................................................................27 1.4.1 La structure de la rhodopsine et les RCPG.........................................................27 1.4.2 Analyse des segments transmembranaires de la famille de la rhodopsine.........28 1.4.3 Les déformations des hélices de la rhodopsine ..................................................30 1.4.3.1 Hélice transmembranaire 1.............................................................................31 1.4.3.2 Hélice transmembranaire 2.............................................................................32 2 1.4.3.3 Hélice transmembranaire 3.............................................................................32 1.4.3.4 Hélice transmembranaire 4.............................................................................34 1.4.3.5 Hélice transmembranaire 5.............................................................................34 1.4.3.6 Hélice transmembranaire 6.............................................................................34 1.4.3.7 Hélice transmembranaire 7.............................................................................35 1.4.4 Conclusion..........................................................................................................35 2 OUTILS MIS EN PLACE..................................................................................................36 2.1 Outils d’analyse de la PDB ........................................................................................37 2.1.1 Outils d’analyse structurale et stéréochimique...................................................37 2.1.1.1 Calcul des angles dièdres ...............................................................................37 2.1.1.2 Calcul des vecteurs normaux parallèles à l’axe d’un segment d’hélice.........39 2.1.1.3 Calcul des angles d’inclinaison et de giration entre 2 hélices successives ....39 2.1.2 Outils d’analyse des séquences ..........................................................................41 2.1.2.1 Formule pour le calcul de la propension des acides aminés...........................41 2.1.2.2 Formule Z-score pour analyser les propensions.............................................41 2.1.2.3 Prédiction des conformations.........................................................................43 2.1.3 La base de données des motifs de hélices cassées : HXH..................................43 2.1.4 Recherche de motifs : SPASM...........................................................................45 2.2 Création de la base de données relationnelle des RCPG............................................46 2.2.1 Modèle conceptuel de données (MCD)..............................................................47 2.3 Conclusion..................................................................................................................49 3 RESULTATS .....................................................................................................................50 3.1 L’analyse du motif hélice-X-hélice au sein des protéines solubles............................51 3.1.1 Article I ..............................................................................................................51 3.1.2 Conclusion..........................................................................................................74 3.2 L’évolution de l’hélice transmembranaire 2 chez les RCPG .....................................76 3.2.1 Article II ............................................................................................................76 3.2.2 Conclusion..........................................................................................................95 4 CONCLUSIONS ET PERSPECTIVES.............................................................................96 LISTE DES ABREVIATIONS................................................................................................100 3 A Marie et Charlotte. 4 REMERCIEMENTS Au terme de ce travail, je tiens à remercier Mme le Dr. Marie Chabbert qui m’a accueilli dans l’équipe de Bioinformatique. Elle m’a donné le goût de la recherche et m’a toujours encouragée. Ses conseils, son encadrement et les nombreuses discussions que nous avons eues, scientifiques ou non, m’ont toujours été bénéfiques. Que vous trouviez dans ce manuscrit le témoignage de ma profonde et sincère reconnaissance. Je remercie M le Dr. Daniel Henrion pour m’avoir accueilli dans son unité de recherche. Je remercie M. le Dr Gibrat et Mme le Dr Milazzo qui ont accepté d’être rapporteurs de mon travail. Je remercie M. le Pr. Delamarche et M. le Dr. Legros qui ont bien voulu participer au jury. Je remercie Mme Chartier, administrateur délégué régional INSERM, pour m’avoir permis de réussir mon transfert de laboratoire. Je remercie les étudiants de l’équipe de bioinformatique avec qui j’ai travaillé pour leur disponibilité et leur gentillesse, ainsi que l’ensemble de l’UMR CNRS 6214/ INSERM 771 pour les séances de bavardages toujours positives, que ce soit humainement ou scientifiquement. Un merci particulier à Mme le Dr Fromy pour son amitié et les longues discussions que nous avons pu partager. Je remercie David Perret, Fabien Barbier et François Rousseau, mes anciens collègues de l’Unité INSERM 564 avec qui je garde toujours de bons contacts. J’espère ne jamais rompre nos liens. Je remercie Francky, toujours enjoué à accepter mes invitations
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