GPCR-I-TASSER: A Hybrid Approach to G Protein-Coupled Receptor Structure Modeling and the Application to the Human Genome

Experimental structure determination remains difficult for G protein-coupled receptors (GPCRs). We propose a new hybrid protocol to construct GPCR structure models that integrates experimental mutagenesis data with ab initio transmembrane (TM) helix assembly simulations. The method was tested on 24 known GPCRs where the ab initio TM-helix assembly procedure constructed the correct fold for 20 cases. When combined with weak homology and sparse mutagenesis restraints, the method generated correct folds for all the tested cases with an average Cα root-mean-square deviation 2.4 Å in the TM regions. The new hybrid protocol was applied to model all 1,026 GPCRs in the human genome, where 923 have a high confidence score and are expected to have correct folds; these contain many pharmaceutically important families with no previously solved structures, including Trace amine, Prostanoids, Releasing hormones, Melanocortins, Vasopressin, and Neuropeptide Y receptors. The results demonstrate new progress on genome-wide structure modeling of TM proteins. •New approach to ab initio GPCR structure assembly•Use of mutagenesis data to assist 3D structure construction•High-resolution structure models for 923 human GPCRs•Provide reliably model for GPCR families that have no experimental structure Zhang et al. developed a hybrid approach, GPCR-I-TASSER, for GPCR structure predictions, which combines experimental mutagenesis data with ab initio transmembrane helix assembly simulations. The method was applied to 1,026 GPCRs in the human genome, with successfully modeled targets containing many pharmaceutically important families with no previously solved structures.