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Homology Modeling of Class A G-Protein-Coupled Receptors in the Age of the Structure Boom

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Computational Design of Membrane Proteins

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2315))

Abstract

With 700 members, G protein-coupled receptors (GPCRs) of the rhodopsin family (class A) form the largest membrane receptor family in humans and are the target of about 30% of presently available pharmaceutical drugs. The recent boom in GPCR structures led to the structural resolution of 57 unique receptors in different states (39 receptors in inactive state only, 2 receptors in active state only and 16 receptors in different activation states). In spite of these tremendous advances, most computational studies on GPCRs, including molecular dynamics simulations, virtual screening and drug design, rely on GPCR models obtained by homology modeling. In this protocol, we detail the different steps of homology modeling with the MODELLER software, from template selection to model evaluation. The present structure boom provides closely related templates for most receptors. If, in these templates, some of the loops are not resolved, in most cases, the numerous available structures enable to find loop templates with similar length for equivalent loops. However, simultaneously, the large number of putative templates leads to model ambiguities that may require additional information based on multiple sequence alignments or molecular dynamics simulations to be resolved. Using the modeling of the human bradykinin receptor B1 as a case study, we show how several templates are managed by MODELLER, and how the choice of template(s) and of template fragments can improve the quality of the models. We also give examples of how additional information and tools help the user to resolve ambiguities in GPCR modeling.

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Acknowledgments

This study was supported by institutional grants from INSERM, CNRS and University of Angers. This work was granted access to HPC resources of IDRIS (GENCI grant 100567 to MC). MC is supported by CNRS. AT is supported by a fellowship from the University of Carthage (Tunisia). RB is supported by a fellowship from the University of Angers (France).

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Author notes

  1. Rym Ben Boubaker

    Present address: UMR CNRS 6015 – INSERM 1083, Laboratoire MITOVASC, Université d’Angers, Angers, France

  2. Asma Tiss

    Present address: Laboratoire de Génétique, Immunologie et Pathologies Humaines, Département de Biologie, Faculté des Sciences de Tunis, Université de Tunis El Manar, Tunis, Tunisie

  3. Asma Tiss and Rym Ben Boubaker contributed equally to this work.

Authors and Affiliations

  1. UMR CNRS 6015 – INSERM 1083, Laboratoire MITOVASC, Université d’Angers, Angers, France

    Asma Tiss, Daniel Henrion & Marie Chabbert

  2. Laboratoire de Génétique, Immunologie et Pathologies Humaines, Département de Biologie, Faculté des Sciences de Tunis, Université de Tunis El Manar, Tunis, Tunisie

    Hajer Guissouma

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  1. Asma Tiss
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Correspondence to Marie Chabbert .

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Editors and Affiliations

  1. Department of Life Sciences, University of Coimbra, Coimbra, Portugal

    Irina S. Moreira

  2. BioISI, University of Lisboa, Lisboa, Portugal

    Miguel Machuqueiro

  3. Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Joana Mourão

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Tiss, A., Ben Boubaker, R., Henrion, D., Guissouma, H., Chabbert, M. (2021). Homology Modeling of Class A G-Protein-Coupled Receptors in the Age of the Structure Boom. In: Moreira, I.S., Machuqueiro, M., Mourão, J. (eds) Computational Design of Membrane Proteins. Methods in Molecular Biology, vol 2315. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1468-6_5

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  • DOI: https://doi.org/10.1007/978-1-0716-1468-6_5

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