8w1l
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Structure of CSF1R kinase domain in complex with Cpd 32== | |
| + | <StructureSection load='8w1l' size='340' side='right'caption='[[8w1l]], [[Resolution|resolution]] 2.26Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8w1l]] is a 1 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=8W1L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8W1L FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.26Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AE3:[3-({3-methoxy-4-[(6-methoxypyridin-3-yl)methoxy]phenyl}methyl)-3H-imidazo[4,5-b]pyridin-6-yl](2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone'>A1AE3</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=8w1l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8w1l OCA], [https://pdbe.org/8w1l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8w1l RCSB], [https://www.ebi.ac.uk/pdbsum/8w1l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8w1l ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/CSF1R_HUMAN CSF1R_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:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</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:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref> Defects in CSF1R are the cause of leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) [MIM:[https://omim.org/entry/221820 221820]. An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes.<ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref> <ref>PMID:22197934</ref> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/CSF1R_HUMAN CSF1R_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and 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 in response to IL34 and CSF1, 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 and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor.<ref>PMID:7683918</ref> <ref>PMID:12882960</ref> <ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:16170366</ref> <ref>PMID:18467591</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:20489731</ref> <ref>PMID:20829061</ref> <ref>PMID:20504948</ref> <ref>PMID:16337366</ref> <ref>PMID:19193011</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Colony stimulating factor-1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors. Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo[4,5-b]pyridine scaffold. Initial structure-activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat. | ||
| - | + | Identification of Selective Imidazopyridine CSF1R Inhibitors.,Kane JL Jr, Asmussen G, Batchelor J, Cromwell M, Fezoui M, Fitzgerald M, Giese B, Gladysheva T, Holley S, Keefe K, Kothe M, Lam B, Lim S, Liu J, Ma L, Metz M, Scholte AA, Shum P, Wei L, Woodworth L, Edling A ACS Med Chem Lett. 2024 Apr 30;15(5):722-730. doi: , 10.1021/acsmedchemlett.4c00110. eCollection 2024 May 9. PMID:38746878<ref>PMID:38746878</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8w1l" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Chodaparambil J]] | ||
| + | [[Category: Kothe M]] | ||
Current revision
Structure of CSF1R kinase domain in complex with Cpd 32
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