title: Quantification of structural distortions in the transmembrane helices of GPCRs.
abstract: A substantial part of the structural and much of the functional information about G protein-coupled receptors (GPCRs) comes from studies on rhodopsin. Thus, analysis tools for detailed structure comparison are key to see to what extent this information can be extended to other GPCRs. Among the methods to evaluate protein structures and, in particular, helix distortions, HELANAL has the advantage that it provides data (local bend and twist angles) that can be easily translated to structural effects, as a local opening/tightening of the helix.In this work I show how HELANAL can be used to extract detailed structural information of the transmembrane bundle of GPCRs, and I provide some examples on how these data can be interpreted to study basic principles of protein structure, to compare homologous proteins and to study mechanisms of receptor activation. Also, I show how in combination with the sequence analysis tools provided by the program GMoS, distortions in individual receptors can be put in the context of the whole Class A GPCR family. Specifically, quantification of the strong proline-induced distortions in the transmembrane bundle of rhodopsin shows that they are not standard proline kinks. Moreover, the helix distortions in transmembrane helix (TMH) 5 and TMH 6 of rhodopsin are also present in the rest of GPCR crystal structures obtained so far, and thus, rhodopsin-based homology models have modeled correctly these strongly distorted helices. While in some cases the inherent "rhodopsin bias" of many of the GPCR models to date has not been a disadvantage, the availability of more templates will clearly result in better homology models. This type of analysis can be, of course, applied to any protein, and it may be particularly useful for the structural analysis of other membrane proteins. A detailed knowledge of the local structural changes related to ligand binding and how they are translated into larger-scale movements of transmembrane domains is key to understand receptor activation.
authors.affiliation: Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen, Switzerland. xavier.deupi@psi.ch
authors.forename: Xavier
authors.initials: X
authors.lastname: Deupi
mesh_terms: D000818:Animals; D002417:Cattle; D019295:Computational Biology / Q000379:methods*; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry
chemical_list: D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D012243:Rhodopsin