ArticleProteins2013
Critical analysis of the successes and failures of homology models of G protein-coupled receptors.
Article in Proteins, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 24 citations in OpenAlex.
- Article
- Influence of the Structural Accuracy of Homology Models on Their Applicability to Docking-Based Virtual Screening: The βJournal of chemical information and modeling · 2019Article
- Structure and activation of the TSH receptor transmembrane domain.Auto- immunity highlights · 2017Article
- Homology modeling of a Class A GPCR in the inactive conformation: A quantitative analysis of the correlation between model/template sequence identity and model accuracy.Journal of molecular graphics & modelling · 2016Article
- Toward high-resolution computational design of the structure and function of helical membrane proteins.Nature structural & molecular biology · 2016Article
- Improving homology modeling of G-protein coupled receptors through multiple-template derived conserved inter-residue interactions.Journal of computer-aided molecular design · 2015Article
- Anti-HIV small-molecule binding in the peptide subpocket of the CXCR4:CVX15 crystal structure.Chembiochem : a European journal of chemical biology · 2014Article
- High-resolution modeling of transmembrane helical protein structures from distant homologues.PLoS computational biology · 2014Article
- Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the Venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior.The Journal of biological chemistry · 2014Article
- SuperBiHelix method for predicting the pleiotropic ensemble of G-protein-coupled receptor conformations.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Discovery and computer aided potency optimization of a novel class of small molecule CXCR4 antagonists.PloS one · 2013Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.