title: Critical analysis of the successes and failures of homology models of G protein-coupled receptors.
abstract: 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.
authors.affiliation: Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
authors.forename: Supriyo
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Alfonso Ramon
authors.initials: AR
authors.lastname: Lam
authors.forename: Hubert
authors.initials: H
authors.lastname: Li
authors.forename: Gouthaman
authors.initials: G
authors.lastname: Balaraman
authors.forename: Michiel Jacobus Maria
authors.initials: MJ
authors.lastname: Niesen
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Vaidehi
mesh_terms: D001665:Binding Sites; D018492:Dopamine Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D012457:Salicylamides / Q000737:chemistry / Q000494:pharmacology; D040681:Structural Homology, Protein
chemical_list: D018492:Dopamine Antagonists; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D019718:Receptors, CXCR4; D050637:Receptors, Dopamine D3; D043562:Receptors, G-Protein-Coupled; D012457:Salicylamides; C045989:eticlopride