title: Interaction of chemokine receptor CXCR4 in monomeric and dimeric state with its endogenous ligand CXCL12: coarse-grained simulations identify differences.
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.
authors.affiliation: a UMR996 - Inflammation, Chemokines and Immunopathology , Inserm, Université Paris-Sud, Université Paris-Saclay , Clamart , France.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Cutolo
authors.affiliation: b LAMBE - UMR 8587, Université d'Evry-Val-d'Essonne, CNRS , Evry , France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Basdevant
authors.affiliation: c BioCIS - UMR 8076, Université Paris-Sud, CNRS, Université Paris-Saclay , Châtenay-Malabry , France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bernadat
authors.affiliation: a UMR996 - Inflammation, Chemokines and Immunopathology , Inserm, Université Paris-Sud, Université Paris-Saclay , Clamart , France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bachelerie
authors.affiliation: c BioCIS - UMR 8076, Université Paris-Sud, CNRS, Université Paris-Saclay , Châtenay-Malabry , France.
authors.forename: Tâp
authors.initials: T
authors.lastname: Ha-Duong
mesh_terms: D001665:Binding Sites; D054377:Chemokine CXCL12 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D019718:Receptors, CXCR4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D054377:Chemokine CXCL12; D008024:Ligands; D019718:Receptors, CXCR4
keywords: CXCR4-CXCL12 quaternary structure; G-protein-coupled receptor; coarse-grained model; molecular dynamics simulation; protein–protein docking