Structure prediction of class A GPCRs.

摘要

Structural models of G-protein-coupled receptors (GPCRs) are valuable in providing insights into the structure-function relationship, and for their potential application in structure-based drug discovery. The challenge in modeling GPCRs is in building reliable models given a small number of template structures and an expected structural diversity around the ligand binding site. An implicit membrane generalized Born (GB) force field had recently been developed and shown to be effective in the folding and assembly of membrane proteins (Im et al. 2003). I began my thesis project exploring the use of this implicit membrane force field in an improved protocol for modeling GPCRs. This thesis describes the development and application of a protocol (foldGPCR) for modeling the class A GPCRs. The protocol aims to accurately model the structural divergence between the template and the target, by using tertiary restraints derived from the template structure, and a refinement method based on the implicit membrane GB force field. The foldGPCR protocol is applied to several members of the class A GPCRs and demonstrated to accurately capture some of the structural features unique to the target. The community-wide GPCR Dock assessment organized in coordination with the release of the most recent crystal structure of a GPCR highlighted the remaining challenges for GPCR structure modeling and docking.