4uai

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of CXCL12 in complex with inhibitor

Structural highlights

4uai is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SDF1_HUMAN Chemoattractant active on T-lymphocytes, monocytes, but not neutrophils. Activates the C-X-C chemokine receptor CXCR4 to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis. Also binds to another C-X-C chemokine receptor CXCR7, which activates the beta-arrestin pathway and acts as a scavenger receptor for SDF-1. SDF-1-beta(3-72) and SDF-1-alpha(3-67) show a reduced chemotactic activity. Binding to cell surface proteoglycans seems to inhibit formation of SDF-1-alpha(3-67) and thus to preserve activity on local sites. Acts as a positive regulator of monocyte migration and a negative regulator of monocyte adhesion via the LYN kinase. Stimulates migration of monocytes and T-lymphocytes through its receptors, CXCR4 and CXCR7, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta-2 integrins. SDF1A/CXCR4 signaling axis inhibits beta-2 integrin LFA-1 mediated adhesion of monocytes to ICAM-1 through LYN kinase. Inhibits CXCR4-mediated infection by T-cell line-adapted HIV-1. Plays a protective role after myocardial infarction. Induces down-regulation and internalization of CXCR7 expressed in various cells. Has several critical functions during embryonic development; required for B-cell lymphopoiesis, myelopoiesis in bone marrow and heart ventricular septum formation.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

CXCL12 binds to CXCR4, promoting both chemotaxis of lymphocytes and metastasis of cancer cells. We previously identified small molecule ligands that bind CXCL12 and block CXCR4-mediated chemotaxis. We now report a 1.9 Angstrom resolution X-ray structure of CXCL12 bound by such a molecule at a site normally bound by sY21 of CXCR4. The complex structure reveals binding hot spots for future inhibitor design and suggests a new approach to targeting CXCL12-CXCR4 signaling in drug discovery.

Structural analysis of a novel small molecule ligand bound to the CXCL12 chemokine.,Smith E, Liu Y, Getschman AE, Peterson F, Ziarek JJ, Li R, Volkman BF, Chen Y J Med Chem. 2014 Oct 30. PMID:25356720^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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
↑ Moepps B, Braun M, Knopfle K, Dillinger K, Knochel W, Gierschik P. Characterization of a Xenopus laevis CXC chemokine receptor 4: implications for hematopoietic cell development in the vertebrate embryo. Eur J Immunol. 2000 Oct;30(10):2924-34. PMID:11069075
↑ Braun M, Wunderlin M, Spieth K, Knochel W, Gierschik P, Moepps B. Xenopus laevis Stromal cell-derived factor 1: conservation of structure and function during vertebrate development. J Immunol. 2002 Mar 1;168(5):2340-7. PMID:11859124
↑ Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem. 2005 Oct 21;280(42):35760-6. Epub 2005 Aug 17. PMID:16107333 doi:M508234200
↑ Malik M, Chen YY, Kienzle MF, Tomkowicz BE, Collman RG, Ptasznik A. Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1 alpha through Lyn kinase. J Immunol. 2008 Oct 1;181(7):4632-7. PMID:18802065
↑ Kalatskaya I, Berchiche YA, Gravel S, Limberg BJ, Rosenbaum JS, Heveker N. AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol Pharmacol. 2009 May;75(5):1240-7. doi: 10.1124/mol.108.053389. Epub 2009 Mar , 2. PMID:19255243 doi:10.1124/mol.108.053389
↑ Smith E, Liu Y, Getschman AE, Peterson F, Ziarek JJ, Li R, Volkman BF, Chen Y. Structural analysis of a novel small molecule ligand bound to the CXCL12 chemokine. J Med Chem. 2014 Oct 30. PMID:25356720 doi:http://dx.doi.org/10.1021/jm501194p

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4uai"

Categories: Homo sapiens | Large Structures | Chen Y | Smith EW

@@ Line 1: / Line 1: @@
 ==Crystal structure of CXCL12 in complex with inhibitor==
-<StructureSection load='4uai' size='340' side='right' caption='[[4uai]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+<StructureSection load='4uai' size='340' side='right'caption='[[4uai]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4uai]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UAI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UAI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4uai]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UAI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UAI FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3GG:1-PHENYL-3-[4-(1H-TETRAZOL-5-YL)PHENYL]UREA'>3GG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4uai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uai OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4uai RCSB], [http://www.ebi.ac.uk/pdbsum/4uai PDBsum]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3GG:1-PHENYL-3-[4-(1H-TETRAZOL-5-YL)PHENYL]UREA'>3GG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4uai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uai OCA], [https://pdbe.org/4uai PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4uai RCSB], [https://www.ebi.ac.uk/pdbsum/4uai PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4uai ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/SDF1_HUMAN SDF1_HUMAN]] Chemoattractant active on T-lymphocytes, monocytes, but not neutrophils. Activates the C-X-C chemokine receptor CXCR4 to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis. Also binds to another C-X-C chemokine receptor CXCR7, which activates the beta-arrestin pathway and acts as a scavenger receptor for SDF-1. SDF-1-beta(3-72) and SDF-1-alpha(3-67) show a reduced chemotactic activity. Binding to cell surface proteoglycans seems to inhibit formation of SDF-1-alpha(3-67) and thus to preserve activity on local sites. Acts as a positive regulator of monocyte migration and a negative regulator of monocyte adhesion via the LYN kinase. Stimulates migration of monocytes and T-lymphocytes through its receptors, CXCR4 and CXCR7, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta-2 integrins. SDF1A/CXCR4 signaling axis inhibits beta-2 integrin LFA-1 mediated adhesion of monocytes to ICAM-1 through LYN kinase. Inhibits CXCR4-mediated infection by T-cell line-adapted HIV-1. Plays a protective role after myocardial infarction. Induces down-regulation and internalization of CXCR7 expressed in various cells. Has several critical functions during embryonic development; required for B-cell lymphopoiesis, myelopoiesis in bone marrow and heart ventricular septum formation.<ref>PMID:8752281</ref> <ref>PMID:11069075</ref> <ref>PMID:11859124</ref> <ref>PMID:16107333</ref> <ref>PMID:18802065</ref> <ref>PMID:19255243</ref>
+[https://www.uniprot.org/uniprot/SDF1_HUMAN SDF1_HUMAN] Chemoattractant active on T-lymphocytes, monocytes, but not neutrophils. Activates the C-X-C chemokine receptor CXCR4 to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis. Also binds to another C-X-C chemokine receptor CXCR7, which activates the beta-arrestin pathway and acts as a scavenger receptor for SDF-1. SDF-1-beta(3-72) and SDF-1-alpha(3-67) show a reduced chemotactic activity. Binding to cell surface proteoglycans seems to inhibit formation of SDF-1-alpha(3-67) and thus to preserve activity on local sites. Acts as a positive regulator of monocyte migration and a negative regulator of monocyte adhesion via the LYN kinase. Stimulates migration of monocytes and T-lymphocytes through its receptors, CXCR4 and CXCR7, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta-2 integrins. SDF1A/CXCR4 signaling axis inhibits beta-2 integrin LFA-1 mediated adhesion of monocytes to ICAM-1 through LYN kinase. Inhibits CXCR4-mediated infection by T-cell line-adapted HIV-1. Plays a protective role after myocardial infarction. Induces down-regulation and internalization of CXCR7 expressed in various cells. Has several critical functions during embryonic development; required for B-cell lymphopoiesis, myelopoiesis in bone marrow and heart ventricular septum formation.<ref>PMID:8752281</ref> <ref>PMID:11069075</ref> <ref>PMID:11859124</ref> <ref>PMID:16107333</ref> <ref>PMID:18802065</ref> <ref>PMID:19255243</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 16: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4uai" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[C-X-C motif chemokine 3D structures|C-X-C motif chemokine 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Chen, Y]]
+[[Category: Homo sapiens]]
-[[Category: Smith, E W]]
+[[Category: Large Structures]]
-[[Category: Chemokine]]
+[[Category: Chen Y]]
-[[Category: Complex]]
+[[Category: Smith EW]]
-[[Category: Cxcl12]]
-[[Category: Inhibitor]]

4uai

From Proteopedia

Current revision

Crystal structure of CXCL12 in complex with inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox