A structural model for how CXCR4 interacts with human CD4 and HIV-1 gp120. Image provided by Ray Stevens.
G protein–coupled receptors (GPCRs) are membrane proteins involved in a broad range of biological processes, and a considerable proportion of clinically used drugs elicit their biological effect(s) via a GPCR. Structural information about GPCRs is quite limited, as the X-ray crystal structures of only two human protein receptors have been solved (the b2 adrenergic and A2A adenosine receptors). Wu et al. now report several X-ray crystal structures of CXCR4, a chemokine receptor that is involved in cancer metastasis and is a key mediator of HIV-1 entry into human cells. The structures are of the GPCR in the presence of IT1t, a drug-like small molecule, or CVX15, a short cyclic peptide that can function as an anti-metastatic therapeutic agent and an inhibitor of HIV-1 entry. The authors identify a number of differences between the structure of CXCR4 and the previously reported structures of GPCRs, including the observation that the ligand-binding pocket of CXCR4 is much larger and closer to the extracellular surface of the protein. The binding sites of IT1t and CVX15 overlap, though CVX15—which is much larger than IT1t—occupies more of the ligand-binding pocket and induces conformational changes in several adjacent helices. CXCR4 is known to form homo- and heterodimers in vivo, and the authors propose that ligand binding to one CXCR4 monomer could induce conformational changes in other CXCR4-associated proteins, modulating receptor function. Additional work is needed to characterize the stoichiometries, structures and in vivo functions of these multimeric complexes, especially because this may reveal new ways to combat HIV infection.