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.
Additional Information
© 2012 Springer Science+Business Media, LLC.Additional details
- Eprint ID
- 34320
- Resolver ID
- CaltechAUTHORS:20120924-135021664
- Sanofi Aventis
- Boehringer-Ingelheim
- Pfizer
- Schering AG
- PharmSelex
- NIH
- Created
-
2012-09-25Created from EPrint's datestamp field
- Updated
-
2021-11-09Created from EPrint's last_modified field
- Series Name
- Methods in Molecular Bology
- Series Volume or Issue Number
- 914