SuperBiHelix: a new method for predicting an ensemble of low-lying GPCR structures

Jenelle Bray, Stanford University

A new procedure called SuperBiHelix has been developed for G protein-coupled receptor (GPCR) structure prediction.  It predicts an ensemble of low-lying structures. SuperBiHelix places predicted TM helices in an experimental template and samples the tilt and sweep angles of the helices along with the rotation of the helices along the helical axes. The procedure was validated on the β2-adrenergic receptor and A2A adenosine receptor experimental crystal structures. The SuperBiHelix procedure will make it possible to more accurately predict structures of GPCRs that are dissimilar to available experimental structures.

SuperBiHelix was used to predict the structure of GPR88, an orphan GPCR with no known ligands that bind to it. It has been identified as a novel target for psychiatric disorders. In order to determine which types of ligands that could bind to it, three low-energy structures were predicted for GPR88. Based on inspection of the structures, lipids were predicted to bind to GPR88. Ligand binding and mutagenesis experiments were suggested that could help to validate the proposed structures and binding sites.

Abstract Author(s): Jenelle Bray, Ravinder Abrol, William A. Goddard III