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Structure prediction of GPCRs using piecewise homologs and application to the human CCR5 chemokine receptor: validation through agonist and antagonist docking
- Source :
- Journal of Biomolecular Structure and Dynamics, Journal of Biomolecular Structure and Dynamics, Taylor & Francis: STM, Behavioural Science and Public Health Titles, 2014, 32, pp.1274-1289. ⟨10.1080/07391102.2013.817952⟩, Journal of Biomolecular Structure and Dynamics, 2014, 32, pp.1274-1289. ⟨10.1080/07391102.2013.817952⟩, Journal of Biomolecular Structure and Dynamics, Taylor & Francis: STM, Behavioural Science and Public Health Titles, 2014, 32 (8), pp.1274-1289. 〈10.1080/07391102.2013.817952〉
- Publication Year :
- 2013
- Publisher :
- Informa UK Limited, 2013.
-
Abstract
- International audience; This article describes the construction and validation of a three-dimensional model of the human CC chemokine receptor 5 (CCR5) receptor using multiple homology modeling. A new methodology is presented where we built each secondary structural model of the protein separately from distantly related homologs of known structure. The reliability of our approach for G-protein coupled receptors was assessed through the building of the human C-X-C chemokine receptor type 4 (CXCR4) receptor of known crystal structure. The models are refined using molecular dynamics simulations and energy minimizations using CHARMM, a classical force field for proteins. Finally, docking models of both the natural agonists and the antagonists of the receptors CCR5 and CXCR4 are proposed. This study explores the possible binding process of ligands to the receptor cavity of chemokine receptors at molecular and atomic levels. We proposed few crucial residues in receptors binding to agonist/antagonist for further validation through experimental analysis. In particular, our study provides better understanding of the blockage mechanism of the chemokine receptors CCR5 and CXCR4, and may help the identification of new lead compounds for drug development in HIV infection, inflammatory diseases, and cancer metastasis.
- Subjects :
- Agonist
Receptors, CXCR4
Receptors, CCR5
medicine.drug_class
Molecular Sequence Data
Computational biology
Protein Structure, Secondary
03 medical and health sciences
Chemokine receptor
0302 clinical medicine
Structural Biology
[ INFO.INFO-BI ] Computer Science [cs]/Bioinformatics [q-bio.QM]
medicine
Amino Acid Sequence
Homology modeling
Receptor
agonist
Molecular Biology
030304 developmental biology
G protein-coupled receptor
CXCR4
0303 health sciences
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]
Chemistry
Interleukin-8 receptor
antagonist
General Medicine
3. Good health
Molecular Docking Simulation
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
molecular dynamics simulation
Biochemistry
Docking (molecular)
030220 oncology & carcinogenesis
CCR5 Receptor Antagonists
docking
Thermodynamics
[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
pairwise homologs
CC chemokine receptors
CCR5
[ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Subjects
Details
- ISSN :
- 15380254 and 07391102
- Volume :
- 32
- Database :
- OpenAIRE
- Journal :
- Journal of Biomolecular Structure and Dynamics
- Accession number :
- edsair.doi.dedup.....56f0e573f846a50a048946f834a30121