Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 2010 Nov 19;330(6007):1066-71
Date
10/12/2010Pubmed ID
20929726Pubmed Central ID
PMC3074590DOI
10.1126/science.1194396Scopus ID
2-s2.0-85027927015 (requires institutional sign-in at Scopus site) 1511 CitationsAbstract
Chemokine receptors are critical regulators of cell migration in the context of immune surveillance, inflammation, and development. The G protein-coupled chemokine receptor CXCR4 is specifically implicated in cancer metastasis and HIV-1 infection. Here we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution. All structures reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface. These structures provide new clues about the interactions between CXCR4 and its natural ligand CXCL12, and with the HIV-1 glycoprotein gp120.
Author List
Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RCAuthor
Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Line
Chemokine CXCL12
Crystallography, X-Ray
HIV Envelope Protein gp120
Humans
Membrane Proteins
Models, Molecular
Protein Binding
Protein Conformation
Protein Multimerization
Receptors, CXCR4
Recombinant Proteins
Spodoptera
Thiourea
