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Mechanism of Activation of a G Protein-Coupled Receptor, the Human Cholecystokinin-2 Receptor

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Mechanism of Activation of a G Protein-Coupled Receptor, the Human Cholecystokinin-2 Receptor Mechanism of Activation of a G Protein-coupled Receptor, the Human Cholecystokinin-2 Receptor Marco, E., Foucaud, M., Langer, I., Escrieut, C., Tikhonova, I. G., & Fourmy, D. (2007). Mechanism of Activation of a G Protein-coupled Receptor, the Human Cholecystokinin-2 Receptor. Journal of Biological Chemistry, 282(39), 28779-28790. https://doi.org/10.1074/jbc.M700349200 Published in: Journal of Biological Chemistry Document Version: Publisher's PDF, also known as Version of record Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal Publisher rights Copyright 2015 Journal of Biological Chemistry General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made to ensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in the Research Portal that you believe breaches copyright or violates any law, please contact [email protected]. Download date:01. Oct. 2021 THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 282, NO. 39, pp. 28779–28790, September 28, 2007 © 2007 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A. Mechanism of Activation of a G Protein-coupled Receptor, the Human Cholecystokinin-2 Receptor* Received for publication, January 12, 2007, and in revised form, June 21, 2007 Published, JBC Papers in Press, June 28, 2007, DOI 10.1074/jbc.M700349200 Esther Marco1,2, Magali Foucaud2, Ingrid Langer1,3, Chantal Escrieut, Irina G. Tikhonova1, and Daniel Fourmy4 From INSERM, Unit 858, Institut Fe´de´ratif de Recherche, 31432 Toulouse, France and the Universite´de Toulouse 3, 31062 Toulouse, France G protein-coupled receptors (GPCRs) represent a major focus ever, these drugs address only a small fraction of the GPCR in functional genomics programs and drug development repertoire. GPCRs represent a major focus in functional research, but their important potential as drug targets contrasts genomics programs and drug development research, but their with the still limited data available concerning their activation important potential as drug targets contrasts strongly with the mechanism. Here, we investigated the activation mechanism of very limited data available regarding their activation mecha- the cholecystokinin-2 receptor (CCK2R). The three-dimen- nism. The activation of GPCRs is generally explained by the sional structure of inactive CCK2R was homology-modeled on extended ternary complex model whereby the population of Downloaded from the basis of crystal coordinates of inactive rhodopsin. Starting receptors exists as an equilibrium between inactive and active from the inactive CCK2R modeled structure, active CCK2R states (1). According to this model, the active conformation of (namely cholecystokinin-occupied CCK2R) was modeled by the receptor may be stabilized or induced by agonists. The means of steered molecular dynamics in a lipid bilayer and by using extended ternary complex model for GPCRs is based on and available data from other GPCRs, including rhodopsin. By compar- sustained by the discovery of engineered constitutively active www.jbc.org ing the modeled structures of the inactive and active CCK2R, we mutants, namely mutants that produce ligand-independent identified changes in the relative position of helices and net- signaling (1). Constitutively active GPCR mutants naturally works of interacting residues, which were expected to stabilize exist in humans and can cause diseases (2). Interestingly, con- either the active or inactive states of CCK2R. Using targeted stitutive GPCR signaling can be inhibited or attenuated by a at QUEENS UNIV, on September 11, 2012 molecular dynamics simulations capable of converting CCK2R class of therapeutic agents named inverse agonists (2, 3). from the inactive to the active state, we delineated structural The cholecystokinin (CCK)-2 receptor (CCK2R), previously changes at the atomic level. The activation mechanism involved named the CCKB/gastrin receptor, belongs to family I of significant movements of helices VI and V, a slight movement of GPCRs, which includes rhodopsin (4–6). It binds both chole- helices IV and VII, and changes in the position of critical resi- cystokinin and gastrin, two structurally related neuropeptides dues within or near the binding site. The mutation of key amino with similar high affinities. CCK2R is expressed in the central acids yielded inactive or constitutively active CCK2R mutants, nervous system and in the gut, where it represents the predom- supporting this proposed mechanism. Such progress in the inant CCK receptor subtype. CCK2R mediates a wide spectrum refinement of the CCK2R binding site structure and in knowl- of CCK- and gastrin-induced biological effects, including anx- edge of CCK2R activation mechanisms will enable target-based iety, pain perception, gastric acid secretion, growth, and differ- optimization of nonpeptide ligands. entiation of the gastric mucosa (4, 7). Converging studies have documented that activation of wild-type CCK2R and/or expression of a constitutively active variant may contribute to The superfamily of G protein-coupled receptors (GPCRs)5 human diseases (8, 9). These new findings have generated con- represents a large and diverse family of seven transmembrane siderable interest in the identification of antagonists of CCK2R. helix proteins. Because they are involved in all physiological To date, a large panel of chemically distinct CCK2R antagonists processes, GPCRs are targeted by 50% of marketed drugs. How- have been discovered and used to assess the functions mediated by CCK2R in animals and humans (10). Furthermore, several of these compounds have reached clinical evaluation stages for * This work was supported in part by Association pour la Recherche contre le Cancer Grants ARC 3282 and 3756. The costs of publication of this article indications such as anxiety and panic disorders, sleep disorders, were defrayed in part by the payment of page charges. This article must drug dependence, pain, gastroesophagus reflux, and gastric therefore be hereby marked “advertisement” in accordance with 18 U.S.C. secretion disorders (10). However, some reference molecules Section 1734 solely to indicate this fact. 1 Supported by fellowships from the “Fondation pour la Recherche Medicale.” believed to be pure antagonists turned out to be endowed with 2 These two authors contributed equally to this work. some agonist activity in the stomach and pancreas as well as 3 “Charge´e de Recherches” from the Fonds National de la Recherche Scienti- cells expressing CCK1R or CCK2R (11–13). On the other hand, fique, Belgium. reports on the expression of constitutively active receptors in 4 To whom correspondence should be addressed: IFR 31, Institut Louis Bug- nard, BP 84225, Unite´ 858, 31432 Toulouse cedex 4, France. E-mail: digestive cancers and on potential therapeutic relevance for [email protected]. neuroendocrine tumors highlighted the need to identify inverse 5 The abbreviations used are: GPCR, G protein-coupled receptor; CCK, chole- agonists able to reverse basal constitutive activity of CCK2R cystokinin; CCK2R, cholecystokinin-2 receptor; MD, molecular dynamics; DMEM, Dulbecco’s modified Eagle’s medium; Ins-P, inositol phosphate; (14). TMD, targeted molecular dynamics; r.m.s., root mean square. Target structure-based design of new ligands requires iden- SEPTEMBER 28, 2007•VOLUME 282•NUMBER 39 JOURNAL OF BIOLOGICAL CHEMISTRY 28779 Human Cholecystokinin Receptor-2 Activation Mechanism tification of the receptor binding site and determination of the the temperature and pressure baths were 1.0 and 0.2 ps, respec- activation mechanism. Toward this aim, our group has progres- tively. SHAKE was applied to all bonds involving hydrogen, and sively delineated the binding site of CCK2R using site-directed an integration step of 2 fs was used throughout. The nonbonded mutagenesis combined with molecular modeling approaches pair list was updated every 10 steps. The simulation protocol (15–17). We identified several aromatic residues belonging to a involved a series of progressive energy minimizations followed network presumably critical for CCK2R activation (18). In this by a 20-ps heating phase and a 250-ps equilibration period, last study, differential motion of amino acid side chains within during which secondary structure restraints were applied to the the binding pocket was observed upon in silico binding of dif- transmembrane helices. These restraints were removed during ferent nonpeptide ligands that present distinct pharmacologi- the following 750 ps of data collection. System coordinates were cal features. Nevertheless, due to the intrinsic limitations of the saved every 2 ps for analysis. modeling procedure used, no global change in CCK2R confor- Modeling of the “Active” CCK2R Structure (CCK2R*)—The mation was observed (18). CCK2R° homology model obtained from the rhodopsin crystal The aim of the present study was to increase our knowledge was not directly suitable for docking purposes, because the of the molecular mechanisms whereby CCK2R is activated. For
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