Abstract
G protein-coupled receptors (GPCRs) interact with an extraordinary diversity of ligands by means of their extracellular domains and/or the extracellular part of the transmembrane (TM) segments. Each receptor subfamily has developed specific sequence motifs to adjust the structural characteristics of its cognate ligands to a common set of conformational rearrangements of the TM segments near the G protein binding domains during the activation process. Thus, GPCRs have fulfilled this adaptation during their evolution by customizing a preserved 7TM scaffold through conformational plasticity. We use this term to describe the structural differences near the binding site crevices among different receptor subfamilies, responsible for the selective recognition of diverse ligands among different receptor subfamilies. By comparing the sequence of rhodopsin at specific key regions of the TM bundle with the sequences of other GPCRs we have found that the extracellular region of TMs 2 and 3 provides a remarkable example of conformational plasticity within Class A GPCRs. Thus, rhodopsin-based molecular models need to include the plasticity of the binding sites among GPCR families, since the “quality” of these homology models is intimately linked with the success in the processes of rational drugdesign or virtual screening of chemical databases.
Keywords: helix-helix interaction, Transmembrane Helices, rhodopsin, conformational plasticity, hydrogen bond network
Current Topics in Medicinal Chemistry
Title: Structural Models of Class A G Protein-Coupled Receptors as a Tool for Drug Design: Insights on Transmembrane Bundle Plasticity
Volume: 7 Issue: 10
Author(s): Xavier Deupi, Nicole Dolker, Maria Luz Lopez-Rodriguez, Mercedes Campillo, Juan A. Ballesteros and Leonardo Pardo
Affiliation:
Keywords: helix-helix interaction, Transmembrane Helices, rhodopsin, conformational plasticity, hydrogen bond network
Abstract: G protein-coupled receptors (GPCRs) interact with an extraordinary diversity of ligands by means of their extracellular domains and/or the extracellular part of the transmembrane (TM) segments. Each receptor subfamily has developed specific sequence motifs to adjust the structural characteristics of its cognate ligands to a common set of conformational rearrangements of the TM segments near the G protein binding domains during the activation process. Thus, GPCRs have fulfilled this adaptation during their evolution by customizing a preserved 7TM scaffold through conformational plasticity. We use this term to describe the structural differences near the binding site crevices among different receptor subfamilies, responsible for the selective recognition of diverse ligands among different receptor subfamilies. By comparing the sequence of rhodopsin at specific key regions of the TM bundle with the sequences of other GPCRs we have found that the extracellular region of TMs 2 and 3 provides a remarkable example of conformational plasticity within Class A GPCRs. Thus, rhodopsin-based molecular models need to include the plasticity of the binding sites among GPCR families, since the “quality” of these homology models is intimately linked with the success in the processes of rational drugdesign or virtual screening of chemical databases.
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Cite this article as:
Deupi Xavier, Dolker Nicole, Luz Lopez-Rodriguez Maria, Campillo Mercedes, Ballesteros A. Juan and Pardo Leonardo, Structural Models of Class A G Protein-Coupled Receptors as a Tool for Drug Design: Insights on Transmembrane Bundle Plasticity, Current Topics in Medicinal Chemistry 2007; 7 (10) . https://dx.doi.org/10.2174/156802607780906799
DOI https://dx.doi.org/10.2174/156802607780906799 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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