First structure of a protein-activated GPCR
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Figure: Schematic of the chemokine
receptor in the cellular milieu, including early stages of the HIV-1 entry
process in the background [Artwork by Yekaterina Kadyshevskaya, Stevens
Laboratory, The Scripps Research Institute]. |
Ray Stevens group (The Scripps Research Institute) and collaborators
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. Five independent crystal
structures of CXCR4 in complex with a small molecule antagonist IT1t and a
cyclic peptide CVX15 at 2.5-to-3.2-Å resolution were solved. As the
first structure of protein-activated GPCR, CXCR4 structure differs from other
known GPCR structures in helix bundle and ligand binding pocket. Although in
multiple crystal forms, all five structures reveal a constant homodimer,
which is the first solid observation about a structural GPCR dimer. CXCR4
structures provide new clues about interactions between CXCR4 and its natural
chemokine ligand CXCL12, and with HIV-1 glycoprotein gp120. These results
have implications for developing new therapeutic strategies for cancer and
HIV treatments.
Citation: 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 RC (2010) Structures of the CXCR4 chemokine GPCR
with small-molecule and cyclic peptide antagonists. Science. 2010 Nov 19;
330, 1066-71.
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