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Interaction of chemokine receptor CXCR4 in monomeric and dimeric state with its endogenous ligand CXCL12: coarse-grained simulations identify differences.

Authors
  • Cutolo, Pasquale1
  • Basdevant, Nathalie2
  • Bernadat, Guillaume3
  • Bachelerie, Françoise1
  • Ha-Duong, Tâp3
  • 1 a UMR996 - Inflammation, Chemokines and Immunopathology , Inserm, Université Paris-Sud, Université Paris-Saclay , Clamart , France. , (France)
  • 2 b LAMBE - UMR 8587, Université d'Evry-Val-d'Essonne, CNRS , Evry , France. , (France)
  • 3 c BioCIS - UMR 8076, Université Paris-Sud, CNRS, Université Paris-Saclay , Châtenay-Malabry , France. , (France)
Type
Published Article
Journal
Journal of biomolecular structure & dynamics
Publication Date
February 2017
Volume
35
Issue
2
Pages
399–412
Identifiers
DOI: 10.1080/07391102.2016.1145142
PMID: 26813575
Source
Medline
Keywords
License
Unknown

Abstract

Despite the recent resolutions of the crystal structure of the chemokine receptor CXCR4 in complex with small antagonists or viral chemokine, a description at the molecular level of the interactions between the full-length CXCR4 and its endogenous ligand, the chemokine CXCL12, in relationship with the receptor recognition and activation, is not yet completely elucidated. Moreover, since CXCR4 is able to form dimers, the question of whether the CXCR4-CXCL12 complex has a 1:1 or 2:1 preferential stoichiometry is still an open question. We present here results of coarse-grained protein-protein docking and molecular dynamics simulations of CXCL12 in association with CXCR4 in monomeric and dimeric states. Our proposed models for the 1:1 and 2:1 CXCR4-CXCL12 quaternary structures are consistent with recognition and activation motifs of both partners provided by the available site-directed mutagenesis data. Notably, we observed that in the 2:1 complex, the chemokine N-terminus makes more steady contacts with the receptor residues critical for binding and activation than in the 1:1 structure, suggesting that the 2:1 stoichiometry would favor the receptor signaling activity with respect to the 1:1 association.

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