4ebw

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[[Image:4ebw.png|left|200px]]
 
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{{STRUCTURE_4ebw| PDB=4ebw | SCENE= }}
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==Structure of Focal Adhesion Kinase catalytic domain in complex with novel allosteric inhibitor==
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<StructureSection load='4ebw' size='340' side='right'caption='[[4ebw]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4ebw]] 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=4EBW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EBW FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.65&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0PF:1-ETHYL-8-(4-ETHYLPHENYL)-5-METHYL-1,5-DIHYDROPYRAZOLO[4,3-C][2,1]BENZOTHIAZINE+4,4-DIOXIDE'>0PF</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ebw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ebw OCA], [https://pdbe.org/4ebw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ebw RCSB], [https://www.ebi.ac.uk/pdbsum/4ebw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ebw ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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>
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Focal adhesion kinase (FAK) regulates cell survival and proliferation pathways. Here we report the discovery of a highly selective series of 1,5-dihydropyrazolo[4,3-c][2,1]benzothiazines that demonstrate a novel mode of allosteric inhibition of FAK. These compounds showed slow dissociation from unphosphorylated FAK and were noncompetitive with ATP after long preincubation. Co-crystal structural analysis revealed that the compounds target a novel allosteric site within the C-lobe of the kinase domain, which induces disruption of ATP pocket formation leading to the inhibition of kinase activity. The potency of allosteric inhibition was reduced by phosphorylation of FAK. Coupled SAR analysis revealed that N-substitution of the fused pyrazole is critical to achieve allosteric binding and high selectivity among kinases.
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===Structure of Focal Adhesion Kinase catalytic domain in complex with novel allosteric inhibitor===
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Discovery and characterization of novel allosteric FAK inhibitors.,Iwatani M, Iwata H, Okabe A, Skene RJ, Tomita N, Hayashi Y, Aramaki Y, Hosfield DJ, Hori A, Baba A, Miki H Eur J Med Chem. 2012 Jun 26. PMID:22819505<ref>PMID:22819505</ref>
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{{ABSTRACT_PUBMED_22819505}}
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4ebw" style="background-color:#fffaf0;"></div>
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==About this Structure==
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==See Also==
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[[4ebw]] 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=4EBW OCA].
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*[[Focal adhesion kinase 3D structures|Focal adhesion kinase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:022819505</ref><references group="xtra"/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Non-specific protein-tyrosine kinase]]
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[[Category: Large Structures]]
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[[Category: Aramaki, Y.]]
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[[Category: Aramaki Y]]
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[[Category: Baba, A.]]
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[[Category: Baba A]]
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[[Category: Hayashi, Y.]]
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[[Category: Hayashi Y]]
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[[Category: Hori, A.]]
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[[Category: Hori A]]
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[[Category: Hosfield, D J.]]
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[[Category: Hosfield DJ]]
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[[Category: Iwata, H.]]
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[[Category: Iwata H]]
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[[Category: Iwatani, M.]]
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[[Category: Iwatani M]]
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[[Category: Miki, H.]]
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[[Category: Miki H]]
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[[Category: Okabe, A.]]
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[[Category: Okabe A]]
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[[Category: Skene, R J.]]
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[[Category: Skene RJ]]
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[[Category: Tomita, N.]]
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[[Category: Tomita N]]
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[[Category: Allosteric inhibitor]]
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[[Category: Kinase domain]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Structure of Focal Adhesion Kinase catalytic domain in complex with novel allosteric inhibitor

PDB ID 4ebw

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