Supriyo Bhattacharya and Alfonso Ramon Lam contributed equally to this work.
Critical analysis of the successes and failures of homology models of G protein-coupled receptors
Article first published online: 14 FEB 2013
Copyright © 2012 Wiley Periodicals, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 81, Issue 5, pages 729–739, May 2013
How to Cite
Bhattacharya, S., Lam, A. R., Li, H., Balaraman, G., Niesen, M. J. M. and Vaidehi, N. (2013), Critical analysis of the successes and failures of homology models of G protein-coupled receptors. Proteins, 81: 729–739. doi: 10.1002/prot.24195
- Issue published online: 4 APR 2013
- Article first published online: 14 FEB 2013
- Accepted manuscript online: 8 OCT 2012 04:01AM EST
- Manuscript Accepted: 21 SEP 2012
- Manuscript Revised: 17 SEP 2012
- Manuscript Received: 24 MAY 2012
- G protein-coupled receptor;
- structure prediction;
- homology model refinement;
- GPCRDOCK2010, CXCR4;
- dopamine receptor;
- rigid body optimization
We present a critical assessment of the performance of our homology model refinement method for G protein-coupled receptors (GPCRs), called LITICon that led to top ranking structures in a recent structure prediction assessment GPCRDOCK2010. GPCRs form the largest class of drug targets for which only a few crystal structures are currently available. Therefore, accurate homology models are essential for drug design in these receptors. We submitted five models each for human chemokine CXCR4 (bound to small molecule IT1t and peptide CVX15) and dopamine D3DR (bound to small molecule eticlopride) before the crystal structures were published. Our models in both CXCR4/IT1t and D3/eticlopride assessments were ranked first and second, respectively, by ligand RMSD to the crystal structures. For both receptors, we developed two types of protein models: homology models based on known GPCR crystal structures, and ab initio models based on the prediction method MembStruk. The homology-based models compared better to the crystal structures than the ab initio models. However, a robust refinement procedure for obtaining high accuracy structures is needed. We demonstrate that optimization of the helical tilt, rotation, and translation is vital for GPCR homology model refinement. As a proof of concept, our in-house refinement program LITiCon captured the distinct orientation of TM2 in CXCR4, which differs from that of adrenoreceptors. These findings would be critical for refining GPCR homology models in future. Proteins 2013. © 2012 Wiley Periodicals, Inc.