title: Structural biology. Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine.
abstract: Chemokines and their receptors control cell migration during development, immune system responses, and in numerous diseases, including inflammation and cancer. The structural basis of receptor:chemokine recognition has been a long-standing unanswered question due to the challenges of structure determination for membrane protein complexes. Here, we report the crystal structure of the chemokine receptor CXCR4 in complex with the viral chemokine antagonist vMIP-II at 3.1 angstrom resolution. The structure revealed a 1:1 stoichiometry and a more extensive binding interface than anticipated from the paradigmatic two-site model. The structure helped rationalize a large body of mutagenesis data and together with modeling provided insights into CXCR4 interactions with its endogenous ligand CXCL12, its ability to recognize diverse ligands, and the specificity of CC and CXC receptors for their respective chemokines.
authors.affiliation: University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
authors.affiliation: University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA. thandel@ucsd.edu stevens@usc.edu ikufareva@ucsd.edu.
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.affiliation: University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA.
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Holden
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.affiliation: University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Fenalti
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Huixian
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Bridge Institute. Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.affiliation: Department of Chemistry, Bridge Institute.
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.affiliation: University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: Department of Chemistry, Bridge Institute. Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA. thandel@ucsd.edu stevens@usc.edu ikufareva@ucsd.edu.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.affiliation: University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA. thandel@ucsd.edu stevens@usc.edu ikufareva@ucsd.edu.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Handel
mesh_terms: D000595:Amino Acid Sequence; D054377:Chemokine CXCL12 / Q000737:chemistry; D018925:Chemokines / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008956:Models, Chemical; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D019718:Receptors, CXCR4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D040681:Structural Homology, Protein
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019718:Receptors, CXCR4; C108059:vMIP-II