Document Detail

Critical analysis of the successes and failures of homology models of G protein-coupled receptors.
MedLine Citation:
PMID:  23042299     Owner:  NLM     Status:  MEDLINE    
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.
Supriyo Bhattacharya; Alfonso Ramon Lam; Hubert Li; Gouthaman Balaraman; Michiel Jacobus Maria Niesen; Nagarajan Vaidehi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-02-14
Journal Detail:
Title:  Proteins     Volume:  81     ISSN:  1097-0134     ISO Abbreviation:  Proteins     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-04     Completed Date:  2013-09-18     Revised Date:  2014-05-08    
Medline Journal Info:
Nlm Unique ID:  8700181     Medline TA:  Proteins     Country:  United States    
Other Details:
Languages:  eng     Pagination:  729-39     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
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MeSH Terms
Binding Sites
Dopamine Antagonists / chemistry,  pharmacology
Molecular Docking Simulation
Protein Conformation
Receptors, Adrenergic, beta-2 / chemistry,  metabolism
Receptors, CXCR4 / chemistry,  metabolism
Receptors, Dopamine D3 / chemistry,  metabolism
Receptors, G-Protein-Coupled / chemistry*,  metabolism
Salicylamides / chemistry,  pharmacology
Structural Homology, Protein*
Grant Support
Reg. No./Substance:
0/Dopamine Antagonists; 0/Ligands; 0/Receptors, Adrenergic, beta-2; 0/Receptors, CXCR4; 0/Receptors, Dopamine D3; 0/Receptors, G-Protein-Coupled; 0/Salicylamides; J8M468HBH4/eticlopride

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