|
|
(14 intermediate revisions not shown.) |
Line 1: |
Line 1: |
- | {{Seed}} | |
- | [[Image:2k03.jpg|left|200px]] | |
| | | |
- | <!-- | + | ==Structure of SDF1 in complex with the CXCR4 N-terminus containing a sulfotyrosine at postition 21== |
- | The line below this paragraph, containing "STRUCTURE_2k03", creates the "Structure Box" on the page.
| + | <StructureSection load='2k03' size='340' side='right'caption='[[2k03]]' scene=''> |
- | You may change the PDB parameter (which sets the PDB file loaded into the applet)
| + | == Structural highlights == |
- | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[2k03]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2K03 FirstGlance]. <br> |
- | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr> |
- | --> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</scene></td></tr> |
- | {{STRUCTURE_2k03| PDB=2k03 | SCENE= }}
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2k03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k03 OCA], [https://pdbe.org/2k03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k03 RCSB], [https://www.ebi.ac.uk/pdbsum/2k03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k03 ProSAT]</span></td></tr> |
| + | </table> |
| + | == Disease == |
| + | [https://www.uniprot.org/uniprot/CXCR4_HUMAN CXCR4_HUMAN] Defects in CXCR4 are a cause of WHIM syndrome (WHIM) [MIM:[https://omim.org/entry/193670 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.<ref>PMID:12692554</ref> |
| + | == Function == |
| + | [https://www.uniprot.org/uniprot/CXCR4_HUMAN 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.<ref>PMID:8329116</ref> <ref>PMID:8234909</ref> <ref>PMID:8629022</ref> <ref>PMID:8752280</ref> <ref>PMID:8752281</ref> <ref>PMID:10074102</ref> <ref>PMID:10644702</ref> <ref>PMID:10825158</ref> <ref>PMID:17197449</ref> <ref>PMID:20048153</ref> <ref>PMID:20228059</ref> <ref>PMID:20505072</ref> |
| + | == Evolutionary Conservation == |
| + | [[Image:Consurf_key_small.gif|200px|right]] |
| + | Check<jmol> |
| + | <jmolCheckbox> |
| + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/k0/2k03_consurf.spt"</scriptWhenChecked> |
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| + | <text>to colour the structure by Evolutionary Conservation</text> |
| + | </jmolCheckbox> |
| + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2k03 ConSurf]. |
| + | <div style="clear:both"></div> |
| + | <div style="background-color:#fffaf0;"> |
| + | == Publication Abstract from PubMed == |
| + | Stem cell homing and breast cancer metastasis are orchestrated by the chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4. Here, we report the nuclear magnetic resonance structure of a constitutively dimeric SDF-1 in complex with a CXCR4 fragment that contains three sulfotyrosine residues important for a high-affinity ligand-receptor interaction. CXCR4 bridged the SDF-1 dimer interface so that sulfotyrosines sTyr7 and sTyr12 of CXCR4 occupied positively charged clefts on opposing chemokine subunits. Dimeric SDF-1 induced intracellular Ca2+ mobilization but had no chemotactic activity; instead, it prevented native SDF-1-induced chemotaxis, suggesting that it acted as a potent partial agonist. Our work elucidates the structural basis for sulfotyrosine recognition in the chemokine-receptor interaction and suggests a strategy for CXCR4-targeted drug development. |
| | | |
- | ===Structure of SDF1 in complex with the CXCR4 N-terminus containing a sulfotyrosine at postition 21===
| + | Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12.,Veldkamp CT, Seibert C, Peterson FC, De la Cruz NB, Haugner JC 3rd, Basnet H, Sakmar TP, Volkman BF Sci Signal. 2008 Sep 16;1(37):ra4. PMID:18799424<ref>PMID:18799424</ref> |
| | | |
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| + | </div> |
| + | <div class="pdbe-citations 2k03" style="background-color:#fffaf0;"></div> |
| | | |
- | <!--
| + | ==See Also== |
- | The line below this paragraph, {{ABSTRACT_PUBMED_18799424}}, adds the Publication Abstract to the page
| + | *[[C-X-C motif chemokine 3D structures|C-X-C motif chemokine 3D structures]] |
- | (as it appears on PubMed at http://www.pubmed.gov), where 18799424 is the PubMed ID number.
| + | *[[CXC chemokine receptor|CXC chemokine receptor]] |
- | -->
| + | *[[CXC chemokine receptor type 4|CXC chemokine receptor type 4]] |
- | {{ABSTRACT_PUBMED_18799424}}
| + | *[[Stromal Derived Factor 1|Stromal Derived Factor 1]] |
- | | + | == References == |
- | ==Disease== | + | <references/> |
- | Known disease associated with this structure: Myelokathexis, isolated OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=162643 162643]], WHIM syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=162643 162643]]
| + | __TOC__ |
- | | + | </StructureSection> |
- | ==About this Structure==
| + | |
- | 2K03 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K03 OCA].
| + | |
- | | + | |
- | ==Reference== | + | |
- | Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12., Veldkamp CT, Seibert C, Peterson FC, De la Cruz NB, Haugner JC 3rd, Basnet H, Sakmar TP, Volkman BF, Sci Signal. 2008 Sep 16;1(37):ra4. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18799424 18799424]
| + | |
| [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
- | [[Category: Protein complex]] | + | [[Category: Large Structures]] |
- | [[Category: Peterson, F C.]] | + | [[Category: Peterson FC]] |
- | [[Category: Veldkamp, C T.]] | + | [[Category: Veldkamp CT]] |
- | [[Category: Volkman, B F.]] | + | [[Category: Volkman BF]] |
- | [[Category: Alternative splicing]]
| + | |
- | [[Category: Chemokine]]
| + | |
- | [[Category: Chemotaxis]]
| + | |
- | [[Category: Cxcl12]]
| + | |
- | [[Category: Cxcr4]]
| + | |
- | [[Category: Cytokine]]
| + | |
- | [[Category: G-protein coupled receptor]]
| + | |
- | [[Category: Glycoprotein]]
| + | |
- | [[Category: Growth factor]]
| + | |
- | [[Category: Host-virus interaction]]
| + | |
- | [[Category: Locked dimer]]
| + | |
- | [[Category: Membrane]]
| + | |
- | [[Category: Receptor]]
| + | |
- | [[Category: Sdf1-alpha]]
| + | |
- | [[Category: Secreted]]
| + | |
- | [[Category: Stromal cell derived factor-1]]
| + | |
- | [[Category: Sulfation]]
| + | |
- | [[Category: Sulfotyrosine]]
| + | |
- | [[Category: Transducer]]
| + | |
- | [[Category: Transmembrane]]
| + | |
- | | + | |
- | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Oct 29 10:44:09 2008''
| + | |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Stem cell homing and breast cancer metastasis are orchestrated by the chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4. Here, we report the nuclear magnetic resonance structure of a constitutively dimeric SDF-1 in complex with a CXCR4 fragment that contains three sulfotyrosine residues important for a high-affinity ligand-receptor interaction. CXCR4 bridged the SDF-1 dimer interface so that sulfotyrosines sTyr7 and sTyr12 of CXCR4 occupied positively charged clefts on opposing chemokine subunits. Dimeric SDF-1 induced intracellular Ca2+ mobilization but had no chemotactic activity; instead, it prevented native SDF-1-induced chemotaxis, suggesting that it acted as a potent partial agonist. Our work elucidates the structural basis for sulfotyrosine recognition in the chemokine-receptor interaction and suggests a strategy for CXCR4-targeted drug development.
Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12.,Veldkamp CT, Seibert C, Peterson FC, De la Cruz NB, Haugner JC 3rd, Basnet H, Sakmar TP, Volkman BF Sci Signal. 2008 Sep 16;1(37):ra4. PMID:18799424[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, Klotman ME, Diaz GA. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet. 2003 May;34(1):70-4. PMID:12692554 doi:10.1038/ng1149
- ↑ Herzog H, Hort YJ, Shine J, Selbie LA. Molecular cloning, characterization, and localization of the human homolog to the reported bovine NPY Y3 receptor: lack of NPY binding and activation. DNA Cell Biol. 1993 Jul-Aug;12(6):465-71. PMID:8329116
- ↑ Jazin EE, Yoo H, Blomqvist AG, Yee F, Weng G, Walker MW, Salon J, Larhammar D, Wahlestedt C. A proposed bovine neuropeptide Y (NPY) receptor cDNA clone, or its human homologue, confers neither NPY binding sites nor NPY responsiveness on transfected cells. Regul Pept. 1993 Sep 22;47(3):247-58. PMID:8234909
- ↑ Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872-7. PMID:8629022
- ↑ Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, Springer TA. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature. 1996 Aug 29;382(6594):829-33. PMID:8752280 doi:10.1038/382829a0
- ↑ Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF, Loetscher M, Baggiolini M, Moser B. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996 Aug 29;382(6594):833-5. PMID:8752281 doi:10.1038/382833a0
- ↑ Brelot A, Heveker N, Adema K, Hosie MJ, Willett B, Alizon M. Effect of mutations in the second extracellular loop of CXCR4 on its utilization by human and feline immunodeficiency viruses. J Virol. 1999 Apr;73(4):2576-86. PMID:10074102
- ↑ Cheng ZJ, Zhao J, Sun Y, Hu W, Wu YL, Cen B, Wu GX, Pei G. beta-arrestin differentially regulates the chemokine receptor CXCR4-mediated signaling and receptor internalization, and this implicates multiple interaction sites between beta-arrestin and CXCR4. J Biol Chem. 2000 Jan 28;275(4):2479-85. PMID:10644702
- ↑ Brelot A, Heveker N, Montes M, Alizon M. Identification of residues of CXCR4 critical for human immunodeficiency virus coreceptor and chemokine receptor activities. J Biol Chem. 2000 Aug 4;275(31):23736-44. PMID:10825158 doi:10.1074/jbc.M000776200
- ↑ Berchiche YA, Chow KY, Lagane B, Leduc M, Percherancier Y, Fujii N, Tamamura H, Bachelerie F, Heveker N. Direct assessment of CXCR4 mutant conformations reveals complex link between receptor structure and G(alpha)(i) activation. J Biol Chem. 2007 Feb 23;282(8):5111-5. Epub 2006 Dec 29. PMID:17197449 doi:10.1074/jbc.C600270200
- ↑ Busillo JM, Armando S, Sengupta R, Meucci O, Bouvier M, Benovic JL. Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling. J Biol Chem. 2010 Mar 5;285(10):7805-17. doi: 10.1074/jbc.M109.091173. Epub 2010 , Jan 4. PMID:20048153 doi:10.1074/jbc.M109.091173
- ↑ Saini V, Marchese A, Majetschak M. CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin. J Biol Chem. 2010 May 14;285(20):15566-76. doi: 10.1074/jbc.M110.103408. Epub, 2010 Mar 12. PMID:20228059 doi:10.1074/jbc.M110.103408
- ↑ Malik R, Marchese A. Arrestin-2 interacts with the endosomal sorting complex required for transport machinery to modulate endosomal sorting of CXCR4. Mol Biol Cell. 2010 Jul 15;21(14):2529-41. doi: 10.1091/mbc.E10-02-0169. Epub, 2010 May 26. PMID:20505072 doi:10.1091/mbc.E10-02-0169
- ↑ Veldkamp CT, Seibert C, Peterson FC, De la Cruz NB, Haugner JC 3rd, Basnet H, Sakmar TP, Volkman BF. Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12. Sci Signal. 2008 Sep 16;1(37):ra4. PMID:18799424 doi:1/37/ra4
|