3oe9
From Proteopedia
Crystal structure of the chemokine CXCR4 receptor in complex with a small molecule antagonist IT1t in P1 spacegroup
Structural highlights
Disease[CXCR4_HUMAN] Defects in CXCR4 are a cause of WHIM syndrome (WHIM) [MIM:193670]; also known as warts, hypogammaglobulinemia, infections and myelokathexis. WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis.[1] Function[CXCR4_HUMAN] Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival. Acts as a coreceptor (CD4 being the primary receptor) for HIV-1 X4 isolates and as a primary receptor for some HIV-2 isolates. Promotes Env-mediated fusion of the virus.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Publication Abstract from PubMedChemokine 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 (GPCRs) 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. Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists.,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 Science. 2010 Oct 7. PMID:20929726[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Lysozyme | ATCG3D, Accelerated Technologies Center for Gene to 3D Structure | Cherezov, V | Chien, E Y.T | GPCR, GPCR Network | Han, G W | Katritch, V | Liu, W | Mol, C D | Stevens, R C | Wu, B | Accelerated technologies center for gene to 3d structure | Atcg3d | Cancer | Chemokine | Chemotaxis | Chimera | Cxcl12 | G protein-coupled receptor | Gpcr | Gpcr network | Hiv-1 co-receptor | Hydrolase | Isothiourea | It1t | Membrane protein | PSI, Protein structure initiative | Psi-biology | Sdf1 | Signal transduction | Signaling protein | Singnaling protein | Structural genomic | T4l fusion | Transmembrane
