title: Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex.
abstract: The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom-resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor-gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, China 201203.
authors.forename: Qiuxiang
authors.initials: Q
authors.lastname: Tan
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Zhuxi
authors.initials: Z
authors.lastname: Chen
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.forename: Limin
authors.initials: L
authors.lastname: Ma
authors.forename: Gustavo
authors.initials: G
authors.lastname: Fenalti
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Wenru
authors.initials: W
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.forename: Beili
authors.initials: B
authors.lastname: Wu
mesh_terms: D001665:Binding Sites; D003510:Cyclohexanes / Q000737:chemistry* / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008024:Ligands; D000077592:Maraviroc; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000737:chemistry* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: C527276:CXCR4 protein, human; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D008024:Ligands; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014230:Triazoles; D000077592:Maraviroc
references.citation: J Biol Chem. 2011 Feb 18;286(7):4978-90
references.pmid: 21118814
references.citation: Virology. 2013 Mar 30;438(1):5-13
references.pmid: 23369572
references.citation: Nat Protoc. 2009;4(5):706-31
references.pmid: 19390528
references.citation: Nature. 2011 Jul 19;477(7366):549-55
references.pmid: 21772288
references.citation: Mol Pharmacol. 2009 Mar;75(3):490-501
references.pmid: 19064629
references.citation: J Med Chem. 2006 May 4;49(9):2784-93
references.pmid: 16640339
references.citation: Science. 2007 Sep 28;317(5846):1930-4
references.pmid: 17901336
references.citation: Nat Immunol. 2001 Feb;2(2):108-15
references.pmid: 11175802
references.citation: J Virol. 2002 Nov;76(21):10791-800
references.pmid: 12368322
references.citation: Science. 2010 Nov 19;330(6007):1066-71
references.pmid: 20929726
references.citation: Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
references.pmid: 15299926
references.citation: Structure. 2012 Jun 6;20(6):967-76
references.pmid: 22681902
references.citation: Curr Opin Infect Dis. 2005 Feb;18(1):9-15
references.pmid: 15647694
references.citation: Nature. 1998 Apr 9;392(6676):565-8
references.pmid: 9560152
references.citation: Methods Enzymol. 1997;276:307-26
references.pmid: 27754618
references.citation: Virology. 2006 Jul 20;351(1):226-36
references.pmid: 16631222
references.citation: Science. 2000 Aug 4;289(5480):739-45
references.pmid: 10926528
references.citation: Mol Pharmacol. 2005 Apr;67(4):1268-82
references.pmid: 15644495
references.citation: J Med Chem. 2006 May 18;49(10):2851-7
references.pmid: 16686527
references.citation: Annu Rev Immunol. 1999;17:657-700
references.pmid: 10358771
references.citation: Science. 2010 Nov 19;330(6007):1091-5
references.pmid: 21097933
references.citation: J Biol Chem. 2000 Aug 4;275(31):23736-44
references.pmid: 10825158
references.citation: Blood. 1999 Sep 15;94(6):1899-905
references.pmid: 10477718
references.citation: AIDS Alert. 2007 Sep;22(9):103
references.pmid: 18411462
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
references.pmid: 20383002
references.citation: J Virol. 1997 Sep;71(9):7136-9
references.pmid: 9261451
references.citation: J Mol Biol. 2007 Jan 26;365(4):1063-75
references.pmid: 17101151
references.citation: J Biol Chem. 2003 Feb 14;278(7):5179-87
references.pmid: 12466283
references.citation: J Virol. 2006 Jun;80(12):6093-105
references.pmid: 16731948
references.citation: Br J Pharmacol. 2012 Mar;165(6):1617-1643
references.pmid: 21699506
references.citation: J Mol Biol. 1994 Jan 21;235(3):983-1002
references.pmid: 8289329
references.citation: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references.pmid: 19461840
references.citation: AIDS Res Hum Retroviruses. 2007 Mar;23(3):415-26
references.pmid: 17411375
references.citation: Annu Rev Pharmacol Toxicol. 2013;53:531-56
references.pmid: 23140243
references.citation: J Biol Chem. 2011 Sep 23;286(38):33409-21
references.pmid: 21775441