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Allosteric Na+-binding site modulates CXCR4 activation

Title
Allosteric Na+-binding site modulates CXCR4 activation
Authors
Cong, XiaojingGolebiowski, Jerome
Issue Date
2018-09
Citation
Physical Chemistry Chemical Physics, 20(38), 24915-24920
Type
Article
Article Type
Article
Keywords
PROTEIN-COUPLED RECEPTORSMU-OPIOID RECEPTORSODIUM-ION BINDINGODORANT RECEPTORSCRYSTAL-STRUCTUREFORCE-FIELDCHEMOKINEINSIGHTSGPCRSIMULATIONS
ISSN
1463-9076
Abstract
G protein-coupled receptors (GPCRs) control most cellular communications with the environment and are the largest protein family of drug targets. As strictly regulated molecular machines, profound comprehension of their activation mechanism is expected to significantly facilitate structure-based drug design. This study provides atomistic-level description of the activation dynamics of the C-X-C chemokine receptor type 4 (CXCR4), a class A GPCR and important drug target. Using molecular dynamics and enhanced sampling, we demonstrate how mutations and protonation of conserved residues trigger activation through microswitches at the receptor core, while sodium ion-a known allosteric modulator-inhibits it. The findings point to a conserved mechanism of activation and the allosteric modulation by sodium in the chemokine receptor family. From the technical aspect, the enhanced sampling protocol effectively samples receptor conformational changes toward activation, and differentiates three variants of the receptor by their basal activity. This work provides structural basis and a powerful in silico tool for CXCR4 agonist design. © 2018 the Owner Societies.
URI
http://hdl.handle.net/20.500.11750/9384
DOI
10.1039/c8cp04134b
Publisher
Royal Society of Chemistry
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