4i4e - Revision history

OCA at 15:14, 20 September 2023

2023-09-20T15:14:47Z

← Older revision		Revision as of 15:14, 20 September 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4i4e]] 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=4I4E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4I4E FirstGlance]. <br>		<table><tr><td colspan='2'>[[4i4e]] 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=4I4E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4I4E FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1BQ:[4-(2-HYDROXYETHYL)PIPERIDIN-1-YL][4-(5-METHYL-4,4-DIOXIDO-1,5-DIHYDROPYRAZOLO[4,3-C][2,1]BENZOTHIAZIN-8-YL)PHENYL]METHANONE'>1BQ</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]] 1.55Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1BQ:[4-(2-HYDROXYETHYL)PIPERIDIN-1-YL][4-(5-METHYL-4,4-DIOXIDO-1,5-DIHYDROPYRAZOLO[4,3-C][2,1]BENZOTHIAZIN-8-YL)PHENYL]METHANONE'>1BQ</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=4i4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i4e OCA], [https://pdbe.org/4i4e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4i4e RCSB], [https://www.ebi.ac.uk/pdbsum/4i4e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4i4e 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=4i4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i4e OCA], [https://pdbe.org/4i4e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4i4e RCSB], [https://www.ebi.ac.uk/pdbsum/4i4e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4i4e ProSAT]</span></td></tr>
	</table>		</table>

OCA at 08:41, 9 November 2022

2022-11-09T08:41:13Z

← Older revision		Revision as of 08:41, 9 November 2022
Line 1:		Line 1:

	==Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.==		==Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.==
	<StructureSection load='4i4e' size='340' side='right' caption='[[4i4e]], [[Resolution\|resolution]] 1.55Å' scene=''>		<StructureSection load='4i4e' size='340' side='right'caption='[[4i4e]], [[Resolution\|resolution]] 1.55Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4i4e]] 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=4I4E OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4I4E FirstGlance]. <br>		<table><tr><td colspan='2'>[[4i4e]] 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=4I4E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4I4E FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1BQ:[4-(2-HYDROXYETHYL)PIPERIDIN-1-YL][4-(5-METHYL-4,4-DIOXIDO-1,5-DIHYDROPYRAZOLO[4,3-C][2,1]BENZOTHIAZIN-8-YL)PHENYL]METHANONE'>1BQ</scene~~></td></tr>~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1BQ:[4-(2-HYDROXYETHYL)PIPERIDIN-1-YL][4-(5-METHYL-4,4-DIOXIDO-1,5-DIHYDROPYRAZOLO[4,3-C][2,1]BENZOTHIAZIN-8-YL)PHENYL]METHANONE'>1BQ</scene></td></tr>
	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ebv\|4ebv]], [[4ebw\|4ebw]], [[4i4f\|4i4f]]</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=4i4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i4e OCA], [https://pdbe.org/4i4e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4i4e RCSB], [https://www.ebi.ac.uk/pdbsum/4i4e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4i4e ProSAT]</span></td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PTK2, FAK, FAK1 ([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/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=4i4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i4e OCA], [~~http~~://pdbe.org/4i4e PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4i4e RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4i4e PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4i4e ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
	[~~[http~~://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.<ref>PMID:11980671</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:17431114</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>		[https://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN] Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.<ref>PMID:11980671</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:17431114</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>
	== Function ==		== Function ==
	[~~[http~~://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.<ref>PMID:10655584</ref> <ref>PMID:11331870</ref> <ref>PMID:11980671</ref> <ref>PMID:15166238</ref> <ref>PMID:15561106</ref> <ref>PMID:15895076</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:16927379</ref> <ref>PMID:17431114</ref> <ref>PMID:18497331</ref> <ref>PMID:18292575</ref> <ref>PMID:18256281</ref> <ref>PMID:18206965</ref> <ref>PMID:19138410</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:20109444</ref> <ref>PMID:21454698</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>		[https://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.<ref>PMID:10655584</ref> <ref>PMID:11331870</ref> <ref>PMID:11980671</ref> <ref>PMID:15166238</ref> <ref>PMID:15561106</ref> <ref>PMID:15895076</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:16927379</ref> <ref>PMID:17431114</ref> <ref>PMID:18497331</ref> <ref>PMID:18292575</ref> <ref>PMID:18256281</ref> <ref>PMID:18206965</ref> <ref>PMID:19138410</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:20109444</ref> <ref>PMID:21454698</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 25:		Line 22:

	==See Also==		==See Also==
	*[[Focal adhesion kinase\|Focal adhesion kinase]]		*[[Focal adhesion kinase 3D structures\|Focal adhesion kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Human~~]]		[[Category: Homo sapiens]]
	[[Category: ~~Non-specific protein-tyrosine kinase~~]]		[[Category: Large Structures]]
	[[Category: Hosfield~~, D J~~]]		[[Category: Hosfield DJ]]
	[[Category: Skene~~, R J]]~~		[[Category: Skene RJ]]
	~~[[Category: Cytoplasmic]]~~
	~~[[Category: Localized to focal adhesion]]~~
	~~[[Category: Phosphorylated on tyrosine]]~~
	~~[[Category: Transferase]]~~
	~~[[Category: Transferase-transferase inhibitor complex~~]]

OCA at 19:14, 4 August 2016

2016-08-04T19:14:32Z

← Older revision		Revision as of 19:14, 4 August 2016
Line 1:		Line 1:

	==Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.==		==Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.==
	<StructureSection load='4i4e' size='340' side='right' caption='[[4i4e]], [[Resolution\|resolution]] 1.55Å' scene=''>		<StructureSection load='4i4e' size='340' side='right' caption='[[4i4e]], [[Resolution\|resolution]] 1.55Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4i4e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I4E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I4E FirstGlance]. <br>		<table><tr><td colspan='2'>[[4i4e]] 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=4I4E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I4E FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1BQ:[4-(2-HYDROXYETHYL)PIPERIDIN-1-YL][4-(5-METHYL-4,4-DIOXIDO-1,5-DIHYDROPYRAZOLO[4,3-C][2,1]BENZOTHIAZIN-8-YL)PHENYL]METHANONE'>1BQ</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1BQ:[4-(2-HYDROXYETHYL)PIPERIDIN-1-YL][4-(5-METHYL-4,4-DIOXIDO-1,5-DIHYDROPYRAZOLO[4,3-C][2,1]BENZOTHIAZIN-8-YL)PHENYL]METHANONE'>1BQ</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ebv\|4ebv]], [[4ebw\|4ebw]], [[4i4f\|4i4f]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ebv\|4ebv]], [[4ebw\|4ebw]], [[4i4f\|4i4f]]</td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PTK2, FAK, FAK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PTK2, FAK, FAK1 ([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/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=4i4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i4e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4i4e RCSB], [http://www.ebi.ac.uk/pdbsum/4i4e 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=4i4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i4e OCA], [http://pdbe.org/4i4e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4i4e RCSB], [http://www.ebi.ac.uk/pdbsum/4i4e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4i4e ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 21:		Line 22:
	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 4i4e" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 28:		Line 30:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Homo sapiens~~]]		[[Category: Human]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Hosfield, D J]]		[[Category: Hosfield, D J]]

OCA at 12:20, 21 December 2014

2014-12-21T12:20:04Z

← Older revision		Revision as of 12:20, 21 December 2014
Line 1:		Line 1:
	~~{{STRUCTURE_4i4e\| PDB=4i4e \| SCENE= }}~~		==Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.==
	===Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.===		<StructureSection load='4i4e' size='340' side='right' caption='[[4i4e]], [[Resolution\|resolution]] 1.55Å' scene=''>
	~~{{ABSTRACT_PUBMED_23414845}}~~		== Structural highlights ==
			<table><tr><td colspan='2'>[[4i4e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I4E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I4E FirstGlance]. <br>
	==Disease==		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1BQ:[4-(2-HYDROXYETHYL)PIPERIDIN-1-YL][4-(5-METHYL-4,4-DIOXIDO-1,5-DIHYDROPYRAZOLO[4,3-C][2,1]BENZOTHIAZIN-8-YL)PHENYL]METHANONE'>1BQ</scene></td></tr>
			<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ebv\|4ebv]], [[4ebw\|4ebw]], [[4i4f\|4i4f]]</td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PTK2, FAK, FAK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
			<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=4i4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i4e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4i4e RCSB], [http://www.ebi.ac.uk/pdbsum/4i4e PDBsum]</span></td></tr>
			</table>
			== Disease ==
	[[http://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.<ref>PMID:11980671</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:17431114</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>		[[http://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.<ref>PMID:11980671</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:17431114</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>
			== Function ==
			[[http://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.<ref>PMID:10655584</ref> <ref>PMID:11331870</ref> <ref>PMID:11980671</ref> <ref>PMID:15166238</ref> <ref>PMID:15561106</ref> <ref>PMID:15895076</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:16927379</ref> <ref>PMID:17431114</ref> <ref>PMID:18497331</ref> <ref>PMID:18292575</ref> <ref>PMID:18256281</ref> <ref>PMID:18206965</ref> <ref>PMID:19138410</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:20109444</ref> <ref>PMID:21454698</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8 -amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC=0.64muM) and in cellular assays (IC=7.1muM). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents.

	~~==Function==~~		Structure-based discovery of cellular-active allosteric inhibitors of FAK.,Tomita N, Hayashi Y, Suzuki S, Oomori Y, Aramaki Y, Matsushita Y, Iwatani M, Iwata H, Okabe A, Awazu Y, Isono O, Skene RJ, Hosfield DJ, Miki H, Kawamoto T, Hori A, Baba A Bioorg Med Chem Lett. 2013 Mar 15;23(6):1779-85. doi: 10.1016/j.bmcl.2013.01.047., Epub 2013 Jan 26. PMID:23414845<ref>PMID:23414845</ref>
	~~[[http://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Non~~-~~receptor protein~~-~~tyrosine kinase that plays an essential role in regulating cell migration~~, ~~adhesion~~, ~~spreading~~, ~~reorganization of the actin cytoskeleton~~, ~~formation and disassembly of focal adhesions and cell protrusions~~, ~~cell cycle progression~~, ~~cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis~~, ~~normal cardiomyocyte migration and proliferation~~, ~~and normal heart development. Regulates axon growth and neuronal cell migration~~, ~~axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction~~, ~~but also in signaling downstream of numerous growth factor receptors~~, ~~G-protein coupled receptors (GPCR)~~, ~~EPHA2~~, ~~netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues~~, ~~creating binding sites for scaffold proteins~~, ~~effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2~~, ~~MAPK3/ERK1 and the MAP kinase signaling cascade~~. ~~Promotes localized and transient activation of guanine nucleotide exchange factors~~ (~~GEFs~~) ~~and GTPase~~-~~activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases~~. ~~Signaling via CAS family members mediates activation of RAC1~~. ~~Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53~~/~~TP53 ubiquitination and proteasomal degradation~~. ~~Phosphorylates SRC; this increases SRC kinase activity~~. ~~Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL~~. ~~Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself~~. ~~Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1~~. ~~Promotes phosphorylation of BMX and PIK3R1~~. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.<ref>PMID:10655584</ref> <ref>PMID:11331870</ref> <ref>PMID:11980671</ref> <ref>PMID:15166238</ref> <ref>PMID:15561106</ref> <ref>PMID:15895076</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:16927379</ref> <ref>PMID:17431114</ref> <ref>PMID:18497331</ref> <ref>PMID:18292575</ref> <ref>PMID:18256281</ref> <ref>PMID:18206965</ref> <ref>PMID:19138410</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:20109444</ref> <ref>PMID:21454698</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:~~19224453~~</ref>

	~~==About this Structure==~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~[[4i4e]] is~~ a ~~1 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http:/~~/~~oca.weizmann.ac.il/oca-bin/ocashort?id=4I4E OCA].~~		</div>

	==~~Reference~~==		==See Also==
	<references ~~group="xtra"~~/><~~references~~/>		*[[Focal adhesion kinase\|Focal adhesion kinase]]
			== References ==
			<references/>
			__TOC__
			</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Hosfield, D J.]]		[[Category: Hosfield, D J]]
	[[Category: Skene, R J.]]		[[Category: Skene, R J]]
	[[Category: Cytoplasmic]]		[[Category: Cytoplasmic]]
	[[Category: Localized to focal adhesion]]		[[Category: Localized to focal adhesion]]

OCA at 10:35, 24 April 2013

2013-04-24T10:35:46Z

← Older revision		Revision as of 10:35, 24 April 2013
Line 1:		Line 1:
	~~[[Image:4i4e.jpg\|left\|200px]]~~

	{{STRUCTURE_4i4e\| PDB=4i4e \| SCENE= }}		{{STRUCTURE_4i4e\| PDB=4i4e \| SCENE= }}
			===Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.===
			{{ABSTRACT_PUBMED_23414845}}

	===~~Structure~~ of ~~Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound~~.~~===~~		==Disease==
			[[http://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.<ref>PMID:11980671</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:17431114</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>

	~~{{ABSTRACT_PUBMED_23414845}}~~		==Function==
			[[http://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.<ref>PMID:10655584</ref> <ref>PMID:11331870</ref> <ref>PMID:11980671</ref> <ref>PMID:15166238</ref> <ref>PMID:15561106</ref> <ref>PMID:15895076</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:16927379</ref> <ref>PMID:17431114</ref> <ref>PMID:18497331</ref> <ref>PMID:18292575</ref> <ref>PMID:18256281</ref> <ref>PMID:18206965</ref> <ref>PMID:19138410</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:20109444</ref> <ref>PMID:21454698</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>

	==About this Structure==		==About this Structure==
	[[4i4e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I4E OCA].		[[4i4e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I4E OCA].

			==Reference==
			<references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]

OCA at 14:16, 6 March 2013

2013-03-06T14:16:18Z

← Older revision		Revision as of 14:16, 6 March 2013
Line 1:		Line 1:
	~~'''Unreleased structure'''~~		[[Image:4i4e.jpg\|left\|200px]]

	~~The entry~~ 4i4e ~~is ON HOLD~~ ~~until Paper Publication~~		{{STRUCTURE_4i4e\| PDB=4i4e \| SCENE= }}

	~~Authors: Skene, R.J., Hosfield, D.J~~.		===Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.===

	~~Description:~~ Structure ~~of Focal Adhesion Kinase catalytic domain in complex~~ with ~~hinge binding pyrazolobenzothiazine compound~~.		{{ABSTRACT_PUBMED_23414845}}

			==About this Structure==
			[[4i4e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I4E OCA].
			[[Category: Homo sapiens]]
			[[Category: Non-specific protein-tyrosine kinase]]
			[[Category: Hosfield, D J.]]
			[[Category: Skene, R J.]]
			[[Category: Cytoplasmic]]
			[[Category: Localized to focal adhesion]]
			[[Category: Phosphorylated on tyrosine]]
			[[Category: Transferase]]
			[[Category: Transferase-transferase inhibitor complex]]

OCA at 11:07, 23 January 2013

2013-01-23T11:07:52Z

← Older revision		Revision as of 11:07, 23 January 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4i4e is ON HOLD		The entry 4i4e is ON HOLD until Paper Publication

	Authors: Skene, R.J., Hosfield, D.J.		Authors: Skene, R.J., Hosfield, D.J.

	Description: Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.		Description: Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.

OCA: Protected "4i4e" [edit=sysop:move=sysop]

2012-12-05T10:33:55Z

Protected "4i4e" [edit=sysop:move=sysop]

← Older revision	Revision as of 10:33, 5 December 2012
(No difference)

OCA: New page: '''Unreleased structure''' The entry 4i4e is ON HOLD Authors: Skene, R.J., Hosfield, D.J. Description: Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding...

2012-12-05T10:33:54Z

New page: '''Unreleased structure''' The entry 4i4e is ON HOLD Authors: Skene, R.J., Hosfield, D.J. Description: Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding...

New page

'''Unreleased structure'''

The entry 4i4e is ON HOLD

Authors: Skene, R.J., Hosfield, D.J.

Description: Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.