title: Structure prediction of G protein-coupled receptors and their ensemble of functionally important conformations.
abstract: G protein-coupled receptors (GPCRs) are integral membrane proteins whose "pleiotropic" nature enables transmembrane (TM) signal transduction, amplification, and diversification via G protein-coupled and β arrestin-coupled pathways. GPCRs appear to enable this by being structurally flexible and by existing in different conformational states with potentially different signaling and functional consequences. We describe a method for the prediction of the three-dimensional structures of these different conformations of GPCRs starting from their amino acid sequence. It combines a unique protocol of computational methods that first predict the TM regions of these receptors and TM helix shapes based on those regions, which is followed by a locally complete sampling of TM helix packings and their scoring that results in a few (~10-20) lowest energy conformations likely to play a role in binding to different ligands and signaling events. Prediction of the structures for multiple conformations of a GPCR is starting to enable the testing of multiple hypotheses related to GPCR activation and binding to ligands with different signaling profiles.
authors.affiliation: Materials and Process Simulation Center, MC, California Institute of Technology, Pasadena, CA, USA. abrol@wag.caltech.edu
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
authors.forename: Adam R
authors.initials: AR
authors.lastname: Griffith
authors.forename: Jenelle K
authors.initials: JK
authors.lastname: Bray
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
mesh_terms: D000595:Amino Acid Sequence; D019295:Computational Biology / Q000379:methods*; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D016415:Sequence Alignment
chemical_list: D043562:Receptors, G-Protein-Coupled