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5lxf
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of the human Macrophage Colony Stimulating Factor M- CSF_C31S variant== | |
| + | <StructureSection load='5lxf' size='340' side='right' caption='[[5lxf]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5lxf]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LXF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LXF FirstGlance]. <br> | ||
| + | </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=5lxf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lxf OCA], [http://pdbe.org/5lxf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lxf RCSB], [http://www.ebi.ac.uk/pdbsum/5lxf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lxf ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/CSF1_HUMAN CSF1_HUMAN]] Note=Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers.<ref>PMID:16337366</ref> <ref>PMID:19934330</ref> Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.<ref>PMID:16337366</ref> <ref>PMID:19934330</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/CSF1_HUMAN CSF1_HUMAN]] Cytokine that plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone development. Required for normal male and female fertility. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration. Plays a role in lipoprotein clearance.<ref>PMID:16337366</ref> <ref>PMID:19934330</ref> <ref>PMID:20829061</ref> <ref>PMID:20504948</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Enhanced activation of the signaling pathways that mediate the differentiation of mononuclear monocytes into osteoclasts is an underlying cause of several bone diseases and bone metastasis. In particular, dysregulation and overexpression of macrophage colony-stimulating factor (M-CSF) and its c-FMS tyrosine kinase receptor, proteins that are essential for osteoclast differentiation, are known to promote bone metastasis and osteoporosis, making both the ligand and its receptor attractive targets for therapeutic intervention. With this aim in mind, our starting point was the previously held concept that the potential of the M-CSFC31S mutant as a therapeutic is derived from its inability to dimerize and hence to act as an agonist. The current study showed, however, that dimerization is not abolished in M-CSFC31S and that the protein retains agonistic activity toward osteoclasts. To design an M-CSF mutant with diminished dimerization capabilities, we solved the crystal structure of the M-CSFC31S dimer complex and used structure-based energy calculations to identify the residues responsible for its dimeric form. We then used that analysis to develop M-CSFC31S,M27R, a ligand-based, high-affinity antagonist for c-FMS that retained its binding ability but prevented the ligand dimerization that leads to receptor dimerization and activation. The monomeric properties of M-CSFC31S,M27R were validated using dynamic light scattering and small-angle X-ray scattering analyses. It was shown that this mutant is a functional inhibitor of M-CSF-dependent c-FMS activation and osteoclast differentiation in vitro Our study, therefore, provided insights into the sequence-structure-function relationships of the M-CSF/c-FMS interaction and of ligand/receptor tyrosine kinase interactions in general. | ||
| - | + | Engineering a monomeric variant of macrophage colony-stimulating factor (M-CSF) that antagonizes the c-FMS receptor.,Zur Y, Rosenfeld L, Bakhman A, Ilic S, Hayun H, Shahar A, Akabayov B, Kosloff M, Levaot N, Papo N Biochem J. 2017 Jul 20;474(15):2601-2617. doi: 10.1042/BCJ20170276. PMID:28655719<ref>PMID:28655719</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5lxf" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Bakhman, A]] | ||
| + | [[Category: Kosloff, M]] | ||
| + | [[Category: Levaot, N]] | ||
| + | [[Category: Papo, N]] | ||
| + | [[Category: Rosenfeld, L]] | ||
| + | [[Category: Shahar, A]] | ||
| + | [[Category: Zarivach, R]] | ||
| + | [[Category: Zur, Y]] | ||
| + | [[Category: Drug design]] | ||
| + | [[Category: Osteoporosis]] | ||
| + | [[Category: Rational protein engineering]] | ||
| + | [[Category: Receptor tyrosine kinase]] | ||
| + | [[Category: Signaling protein]] | ||
Revision as of 04:15, 4 August 2017
Crystal structure of the human Macrophage Colony Stimulating Factor M- CSF_C31S variant
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