G Protein-Coupled Receptors Insights Into Chemokine Receptors

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RESEARCH HIGHLIGHTS G PROTEIN-COUPLED RECEPTORS Insights into chemokine receptors A recent paper published in Science modelling (based on previously has reported the crystal structure of defined GPCR structures) would be the chemokine receptor CXCR4, a difficult. In addition, CXCR4 lacked G protein-coupled receptor (GPCR) several features previously thought to that has been implicated in cancer be common to many GPCRs, such as metastasis and HIV infection. This is a short alpha helix located at the start the first report of a GPCR structure of the carboxyl terminus. that is activated by a protein ligand, CXCR4 is thought to form and it shows considerable differences homo- and hetero-oligomers, and compared with other GPCRs with the structures elucidated in this study known crystal structures. corroborated this. However, CXCR4 The authors determined the crys- oligomers would form in a consider- tal structures of the human CXCR4 ably different way from previous in complex with two antagonists: the models of GPCR oligomerization. small molecule antagonist IT1t and That is, CXCR4 uses helices V and the cyclic peptide inhibitor CVX15. VII to interact and is stabilized by As expected, the overall structure of helices III and IV. Furthermore, the CXCR4 consisted of the canonical structure of CXCR4 supported the bundle of seven transmembrane ‘two site’ model of chemokine signal- helices that are typical of all GPCRs. ling, whereby a core sequence of a The most notable difference between chemokine ligand docks to the bind- CXCR4 and other characterized ing domain of the receptor, and the GPCRs (such as rhodopsin, the amino terminal domain of the ligand β2-adrenergic receptor and the A2A triggers signalling. adenosine receptor) was the different Hopefully, knowledge of the shape and the different location of structure of CXCR4 will provide the ligand binding site. The binding new insights into chemokine cavity was larger, more open and receptor–ligand interactions, such located closer to the extracellular as the interaction of CXCR4 with its surface. It was defined by side chains endogenous ligand CXCL12 (which from helices I, II, III and VII but, inhibits HIV-1 entry) and with the unlike other known GPCR–ligand HIV-1 glycoprotein gp120. complexes, made no contact with Charlotte Harrison helices IV, V and VI. ORIGINAL RESEARCH PAPER Structures There were also differences in the of the CXCR4 chemokine GPCR with small arrangement of the transmembrane molecule and cyclic peptide antagonists. Science 7 Oct 2010 (doi:10.1126/science.1194396) helices, suggesting that homology NATURE REVIEWS | DRUG DISCOVERY VOLUME 9 | DECEMBER 2010 © 2010 Macmillan Publishers Limited. All rights reserved.

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Molecular Signatures of G-Protein-Coupled Receptors A
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commentaries fied mice with minimal or no steady-state Phone: (314) 362-8834; Fax: (314) 362-8826; 7. Socolovsky, M., et al. 2001. Ineffective erythropoie- sis in Stat5a(–/–)5b(–/–) mice due to decreased sur- phenotype. In many ways these mice could E-mail: [email protected]. vival of early erythroblasts. Blood. 98:3261–3273. be viewed as models for otherwise normal 8. Zang, H., et al. 2001. The distal region and receptor adult humans who exhibit exaggerated or 1. Palis, J., and Segel, G.B. 1998. Developmental biol- tyrosines of the Epo receptor are non-essential for ogy of erythropoiesis. Blood Rev. 12:106–114. in vivo erythropoiesis. EMBO J. 20:3156–3166. unexpected responses to inflammation, 2. Obinata, M., and Yanai, N. 1999. Cellular and 9. D’Andrea, A.D., et al. 1991. The cytoplasmic region infectious agents, or cancer progression. molecular regulation of an erythropoietic induc- of the erythropoietin receptor contains nonover- As such, they have the potential to identify tive microenvironment (EIM). Cell Struct. Funct. lapping positive and negative growth-regulatory 24:171–179. and dissect regulatory pathways that influ- domains. Mol. Cell. Biol. 11:1980–1987. 3. Menon, M.P., et al. 2006. Signals for stress erythro- 10. Wagner, K.U., et al. 2000. Conditional deletion of the ence but do not cause disease. poiesis are integrated via an erythropoietin receptor– Bcl-x gene from erythroid cells results in hemolytic phosphotyrosine-343–Stat5 axis. J. Clin. Invest. anemia and profound splenomegaly. Development. Acknowledgments 116:683–694. doi:10.1172/JCI25227. 127:4949–4958. 4. Teglund, S., et al.
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