Comparative Analysis of the Heptahelical Transmembrane Bundles of G Protein-Coupled Receptors

Tetsuji Okada,Roland Seifert

doi:10.1371/journal.pone.0035802

Abstract

BackgroundG protein-coupled receptors represent a large family of eukaryotic membrane proteins, and are involved in almost all physiological processes in humans. Recent advances in the crystallographic study of these receptors enable a detailed comparative analysis of the commonly shared heptahelical transmembrane bundle. Systematic comparison of the bundles from a variety of receptors is indispensable for understanding not only of the structural diversification optimized for the binding of respective ligands but also of the structural conservation required for the common mechanism of activation accompanying the interaction changes among the seven helices.Methodology/Principal FindingsWe have examined the bundles of 94 polypeptide chains from almost all available structures of 11 receptors, which we classified into either inactivated chain or activated chain, based on the type of bound ligand. For the inactivated chains, superposition of 200 residue bundles by secondary structure matching demonstrated that the bound ligands share a laterally limited cavity in the extracellular section of the bundle. Furthermore, a distinct feature was found for helix III of bovine rhodopsin, which might have evolved to lower its activity in the presence of 11-cis-retinal, to a level that other receptors could hardly achieve with any currently available ligands.Conclusions/SignificanceSystematic analysis described here would be valuable for understanding of the rearrangement of seven helices which depends on the ligand specificity and activation state of the receptors.

Highlights

G protein-coupled receptor (GPCR) mediates signal transduction through the cell membrane by activating many copies of cognate heterotrimeric G protein upon binding of an agonist [1]
Each polypeptide chain in an entry was considered separately, giving a total of 94 chains. They were classified into two categories: an inactivated group and an activated group, containing 62 and 32 chains, respectively. This classification is solely based on the type of ligand binding and does not necessarily mean that each chain in the activated group substantially differs with respect to the backbone structure from the inactivated group
To initiate the process of rhodopsin activation, photon energy is required to push the middle of helix III transiently out to a position similar to that observed in the other receptors

Summary

Introduction

G protein-coupled receptor (GPCR) mediates signal transduction through the cell membrane by activating many copies of cognate heterotrimeric G protein upon binding of an agonist [1]. A majority of the GPCR superfamily is grouped into the class A (rhodopsin-like) family which shares a handful of amino acids in the 7TM region. Crystallographic studies have made extensive progress in solving structures for the class A GPCRs for biogenic amines, including turkey b1 and human b2 adrenergic receptors, human dopamine D3 receptor, human histamine H1 receptor, and most recently, human M2 and rat M3 muscarinic acetylcholine receptors [3,4]. Recent advances in the crystallographic study of these receptors enable a detailed comparative analysis of the commonly shared heptahelical transmembrane bundle. Systematic comparison of the bundles from a variety of receptors is indispensable for understanding of the structural diversification optimized for the binding of respective ligands and of the structural conservation required for the common mechanism of activation accompanying the interaction changes among the seven helices

Methods

Results

Conclusion