4r7i - Revision history

OCA at 17:45, 20 September 2023

OCA — Wed, 20 Sep 2023 17:45:18 GMT

←Older revision		Revision as of 17:45, 20 September 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4r7i]] 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=4R7I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R7I FirstGlance]. <br>		<table><tr><td colspan='2'>[[4r7i]] 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=4R7I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R7I FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</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]] 2.75Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</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=4r7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r7i OCA], [https://pdbe.org/4r7i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r7i RCSB], [https://www.ebi.ac.uk/pdbsum/4r7i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r7i ProSAT]</span></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=4r7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r7i OCA], [https://pdbe.org/4r7i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r7i RCSB], [https://www.ebi.ac.uk/pdbsum/4r7i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r7i ProSAT]</span></td></tr>
	</table>		</table>

OCA at 06:43, 2 March 2023

OCA — Thu, 02 Mar 2023 06:43:10 GMT

←Older revision		Revision as of 06:43, 2 March 2023
Line 3:		Line 3:
	<StructureSection load='4r7i' size='340' side='right'caption='[[4r7i]], [[Resolution\|resolution]] 2.75Å' scene=''>		<StructureSection load='4r7i' size='340' side='right'caption='[[4r7i]], [[Resolution\|resolution]] 2.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4r7i]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R7I OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4R7I FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4r7i]] 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=4R7I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R7I FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CSF1R, FMS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4r7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r7i OCA], [https://pdbe.org/4r7i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r7i RCSB], [https://www.ebi.ac.uk/pdbsum/4r7i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r7i ProSAT]</span></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></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=4r7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r7i OCA], [~~http~~://pdbe.org/4r7i PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4r7i RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4r7i PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4r7i ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://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:[~~http~~://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>	+	[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 ==		== Function ==
-	[~~[http~~://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>	+	[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 22:

	==See Also==		==See Also==
-	*[[Colony-stimulating factor receptor\|Colony-stimulating factor receptor]]	+	*[[Colony-stimulating factor receptor 3D structures\|Colony-stimulating factor receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Zhang C]]
-	[[Category: Zhang, C]]	+	[[Category: Zhang Y]]
-	[[Category: Zhang, Y]]	+
-	~~[[Category: Atp-binding]]~~	+
-	~~[[Category: C-fm]]~~	+
-	~~[[Category: Cd115 antigen]]~~	+
-	~~[[Category: Csf-1-r]]~~	+
-	~~[[Category: Fms proto-oncogene]]~~	+
-	~~[[Category: Gleevec]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 09:46, 1 May 2019

OCA — Wed, 01 May 2019 09:46:29 GMT

←Older revision		Revision as of 09:46, 1 May 2019
Line 1:		Line 1:

	==Crystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC==		==Crystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC==
-	<StructureSection load='4r7i' size='340' side='right' caption='[[4r7i]], [[Resolution\|resolution]] 2.75Å' scene=''>	+	<StructureSection load='4r7i' size='340' side='right'caption='[[4r7i]], [[Resolution\|resolution]] 2.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4r7i]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R7I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R7I FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4r7i]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R7I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R7I FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CSF1R, FMS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></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=4r7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r7i OCA], [http://pdbe.org/4r7i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r7i RCSB], [http://www.ebi.ac.uk/pdbsum/4r7i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r7i ProSAT]</span></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=4r7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r7i OCA], [http://pdbe.org/4r7i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r7i RCSB], [http://www.ebi.ac.uk/pdbsum/4r7i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r7i ProSAT]</span></td></tr>
Line 21:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 4r7i" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4r7i" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Colony-stimulating factor receptor\|Colony-stimulating factor receptor]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Zhang, C]]		[[Category: Zhang, C]]

OCA at 16:09, 17 May 2017

OCA — Wed, 17 May 2017 16:09:42 GMT

←Older revision		Revision as of 16:09, 17 May 2017
Line 1:		Line 1:
		+
	==Crystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC==		==Crystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC==
	<StructureSection load='4r7i' size='340' side='right' caption='[[4r7i]], [[Resolution\|resolution]] 2.75Å' scene=''>		<StructureSection load='4r7i' size='340' side='right' caption='[[4r7i]], [[Resolution\|resolution]] 2.75Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</scene></td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></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=4r7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r7i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r7i RCSB], [http://www.ebi.ac.uk/pdbsum/4r7i PDBsum]</span></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=4r7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r7i OCA], [http://pdbe.org/4r7i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r7i RCSB], [http://www.ebi.ac.uk/pdbsum/4r7i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r7i ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 19:		Line 20:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4r7i" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 14:39, 12 August 2015

OCA — Wed, 12 Aug 2015 14:39:24 GMT

←Older revision		Revision as of 14:39, 12 August 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Crystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC==
		+	<StructureSection load='4r7i' size='340' side='right' caption='[[4r7i]], [[Resolution\|resolution]] 2.75Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4r7i]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R7I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R7I FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></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=4r7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r7i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r7i RCSB], [http://www.ebi.ac.uk/pdbsum/4r7i PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://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:[http://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 ==
		+	[[http://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 ==
		+	BACKGROUND: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R). METHODS: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor. RESULTS: A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment. CONCLUSIONS: Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861.).

-	~~The entry 4r7i is ON HOLD until Paper Publication~~	+	Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.,Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, Chmielowski B, Staddon AP, Cohn AL, Shapiro GI, Keedy VL, Singh AS, Puzanov I, Kwak EL, Wagner AJ, Von Hoff DD, Weiss GJ, Ramanathan RK, Zhang J, Habets G, Zhang Y, Burton EA, Visor G, Sanftner L, Severson P, Nguyen H, Kim MJ, Marimuthu A, Tsang G, Shellooe R, Gee C, West BL, Hirth P, Nolop K, van de Rijn M, Hsu HH, Peterfy C, Lin PS, Tong-Starksen S, Bollag G N Engl J Med. 2015 Jul 30;373(5):428-37. doi: 10.1056/NEJMoa1411366. PMID:26222558<ref>PMID:26222558</ref>

-	~~Authors: Zhang~~, Y.~~, Zhang, C~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Crystal structure of FMS~~ kinase ~~domain with a small molecular inhibitor, GLEEVEC~~	+	== References ==
-	[[Category: ~~Unreleased Structures~~]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Zhang, C]]
	[[Category: Zhang, Y]]		[[Category: Zhang, Y]]
-	[[Category: ~~Zhang,~~ C]]	+	[[Category: Atp-binding]]
		+	[[Category: C-fm]]
		+	[[Category: Cd115 antigen]]
		+	[[Category: Csf-1-r]]
		+	[[Category: Fms proto-oncogene]]
		+	[[Category: Gleevec]]
		+	[[Category: Kinase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 16:35, 24 December 2014

OCA — Wed, 24 Dec 2014 16:35:59 GMT

←Older revision		Revision as of 16:35, 24 December 2014
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	Description: Crystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC		Description: Crystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC
		+	[[Category: Unreleased Structures]]
		+	[[Category: Zhang, Y]]
		+	[[Category: Zhang, C]]

OCA at 06:28, 8 October 2014

OCA — Wed, 08 Oct 2014 06:28:14 GMT

←Older revision		Revision as of 06:28, 8 October 2014
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4r7i is ON HOLD	+	The entry 4r7i is ON HOLD until Paper Publication

	Authors: Zhang, Y., Zhang, C.		Authors: Zhang, Y., Zhang, C.

	Description: Crystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC		Description: Crystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC

OCA at 08:24, 10 September 2014

OCA — Wed, 10 Sep 2014 08:24:40 GMT

←Older revision		Revision as of 08:24, 10 September 2014
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	Authors: Zhang, Y., Zhang, C.		Authors: Zhang, Y., Zhang, C.

-	Description: ~~CRYSTAL STRUCTURE OF~~ FMS ~~KINASE DOMAIN WITH A SMALL MOLECULAR INHIBITOR~~, GLEEVEC	+	Description: Crystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC

OCA: Protected "4r7i" [edit=sysop:move=sysop]

OCA — Thu, 04 Sep 2014 04:19:06 GMT

Protected "4r7i" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:19, 4 September 2014

OCA: New page: '''Unreleased structure''' The entry 4r7i is ON HOLD Authors: Zhang, Y., Zhang, C. Description: CRYSTAL STRUCTURE OF FMS KINASE DOMAIN WITH A SMALL MOLECULAR INHIBITOR, GLEEVEC

OCA — Thu, 04 Sep 2014 04:19:05 GMT

New page: '''Unreleased structure''' The entry 4r7i is ON HOLD Authors: Zhang, Y., Zhang, C. Description: CRYSTAL STRUCTURE OF FMS KINASE DOMAIN WITH A SMALL MOLECULAR INHIBITOR, GLEEVEC

New page

'''Unreleased structure'''

The entry 4r7i is ON HOLD

Authors: Zhang, Y., Zhang, C.

Description: CRYSTAL STRUCTURE OF FMS KINASE DOMAIN WITH A SMALL MOLECULAR INHIBITOR, GLEEVEC