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New G-protein-coupled receptor structures provide insights into the recognition of CXCL12 and HIV-1 gp120 by CXCR4.

The G protein-coupled receptor (GPCR) superfamily consists of thousands of integral membrane proteins that exert a wide variety of physiological functions and account for a large portion of the drug targets identified so far. However, structural knowledge of GPCRs is scarce, with crystal structures determined for only a few members including b1 and b2 adrenergic receptors, adenosine receptor, rhodopsin, and dopamine D3 receptor [1]. Recently, Wu et al. published in Science the structure of CXCR4, which is the first structure of the 19 known chemokine receptors of the GPCR superfamily [2]. The widely expressed chemokine receptor CXCR4 is exclusively activated by CXCL12 (also known as SDF-1). The CXCL12/CXCR4 signaling plays important functional roles in various biological processes such as cell trafficking, cell survival, and proliferation, and is essential for the development (reviewed in [3,4]). The CXCL12/CXCR4 axis has also been indicated to be critical for the homing of CXCR4-expressing tumor cells to tissues secreting CXCL12 such as the bone marrow, lung, liver, and lymph nodes, and their survival and proliferation in the new environment [3,4]. Therefore, the CXCL12/CXCR4 pathway is an important drug target for various types of cancers [5], and one small-molecule inhibitor of the pathway, namely Plerixafor has been approved by the US Food and Drug Administration for the treatment of non-Hodgkin lymphoma and multiple myeloma together with granulocyte-colony stimulating factor. In addition, CXCR4 also functions as a co-receptor for the entry of X4 HIV-1 strains and is a validated pharmaceutical target for modulating the viral entry of HIV-1 into T cells [6]. Precise structural information is valuable for design and development of new regimens against diseases. Although CXCR4 is an important drug target, by the time Wu et al. published their results, only one structure of CXCL12 in complex with a peptide derived from the sequence of the N-terminal 38 residues of CXCR4 (p38) was reported [7]. Although the CXCL12-p38 structure elucidated the structural basis for the interaction of CXCL12 with the N-terminus of CXCR4 [7], the structure of CXCR4 is still largely unknown, and the other regions of CXCR4 that potentially interact with CXCL12 has not been identified. Moreover, the dimeric CXCL12-p38 structure might only represent one of the dynamic oligomeric states of the complex. For the fusion of HIV-1, CCR5 is a co-receptor for CD4 for R5 HIV-1 strains, which is also a chemokine receptor of the GPCR superfamily. The structure of the CCR5 N-terminus (residues 2–15) in complex with HIV-1 gp120 and CD4 had been determined recently [8]; however, a similar structure of CXCR4 was not available yet. In the recent paper by Wu et al., five crystal structures of human CXCR4 variants in complexes with a smallmolecule isothiourea derivative, namely 1T15, and with a cyclic peptide inhibitor, namely CVX15 at resolution of 2.5–3.2 A are reported [2]. Comparison of the CXCR4 structures with the previously reported GPCR structures reveals that in CXCR4 the overall architecture of the canonical bundle of seven transmembrane helices is divergent from that in the other GPCR structures with multiple profound differences, underscoring the necessity of obtaining precise structural information with experimentally determined structures rather than constructed homology models. On the extracellular side of CXCR4, the conserved disulfide bonds between Cys28 of the N-terminal segment and Cys274 at the tip of helix VII, and between Cys109 and Cys186 of extracellular loop 2 (ECL2) are found to stabilize the N-terminal segment and ECL2 to form the entrance to the ligand-binding pocket, which explains their critical roles in the ligand binding. On the intracellular side, the intracellular part of helix VII is one turn shorter compared with the other GPCR structures, and helix VIII is missing with the C-terminus taking an extended conformation. The CXCR4 mutant (CXCR4-3) carrying a T240P mutation Acta Biochim Biophys Sin 2011, 43: 337–338 | a The Author 2011. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. DOI: 10.1093/abbs/gmr026. Advance Access Publication 31 March 2011