Structure Prediction of G Protein-Coupled Receptors and Their Ensemble of Functionally Important Conformations.
Ravinder Abrol, A.R. Griffith, Jenelle K. Bray, William A. Goddard III
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.
Group Members
Abrol, R., Griffith, A., Bray, J. K., & III, W. A. G. (2012). Structure Prediction of G Protein-Coupled Receptors and Their Ensemble of Functionally Important Conformations.. *Membrane Protein Structure and Dynamics: Methods and Protocols , N. Vaidehi and J. Klein-Setharaman, Ed. Springer,pp.237–254*. https://doi.org/10.1007/978-1-62703-023-6_14