GPCR-I-TASSER: A Hybrid Approach to G Protein-Coupled Receptor Structure Modeling and the Application to the Human
Jian Zhang1, Jianyi Yang2, Richard Jang1
1Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA.
Structure (London, England : 1993)
|July 21, 2015
Summary
A new hybrid protocol accurately models G protein-coupled receptor (GPCR) structures using mutagenesis data and simulations. This method successfully predicted the folds for most human GPCRs, advancing transmembrane protein structure prediction.
Area of Science:
- Structural biology
- Computational biology
- Biophysics
Background:
- Experimental determination of G protein-coupled receptor (GPCR) structures is challenging.
- GPCRs are crucial membrane proteins involved in numerous physiological processes and drug targets.
Purpose of the Study:
- To develop and validate a novel hybrid protocol for constructing accurate GPCR structure models.
- To apply this protocol for genome-wide structure modeling of human GPCRs.
Main Methods:
- Integration of experimental mutagenesis data with ab initio transmembrane (TM) helix assembly simulations.
- Testing the protocol on 24 known GPCRs to assess accuracy and fold prediction.
- Application to model all 1,026 human GPCRs.
Main Results:
- The ab initio TM-helix assembly correctly predicted the fold for 20 out of 24 tested GPCRs.
- Combining with homology and mutagenesis restraints yielded correct folds for all cases (average Cα RMSD 2.4 Å).
- Successfully modeled 923 out of 1,026 human GPCRs with high confidence, including pharmaceutically relevant families.
Conclusions:
- The hybrid protocol offers a robust approach for GPCR structure modeling.
- Enables genome-wide structural insights into previously uncharacterized GPCR families.
- Represents significant progress in the computational modeling of transmembrane proteins.
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