1opk: Difference between revisions

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-[[Image:1opk.png|left|200px]]
-{{STRUCTURE_1opk|  PDB=1opk  |  SCENE=  }}
+==Structural basis for the auto-inhibition of c-Abl tyrosine kinase==
+<StructureSection load='1opk' size='340' side='right'caption='[[1opk]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1opk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OPK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1OPK 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]] 1.8&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene>, <scene name='pdbligand=P16:6-(2,6-DICHLOROPHENYL)-2-{[3-(HYDROXYMETHYL)PHENYL]AMINO}-8-METHYLPYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>P16</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=1opk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1opk OCA], [https://pdbe.org/1opk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1opk RCSB], [https://www.ebi.ac.uk/pdbsum/1opk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1opk ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/ABL1_MOUSE ABL1_MOUSE] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-191' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks.<ref>PMID:8194526</ref> <ref>PMID:7780740</ref> <ref>PMID:9109492</ref> <ref>PMID:11279004</ref> <ref>PMID:11350980</ref> <ref>PMID:11279131</ref> <ref>PMID:12107171</ref> <ref>PMID:12748290</ref> <ref>PMID:14993293</ref> <ref>PMID:19903482</ref> <ref>PMID:19878872</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/op/1opk_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1opk ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+c-Abl is normally regulated by an autoinhibitory mechanism, the disruption of which leads to chronic myelogenous leukemia. The details of this mechanism have been elusive because c-Abl lacks a phosphotyrosine residue that triggers the assembly of the autoinhibited form of the closely related Src kinases by internally engaging the SH2 domain. Crystal structures of c-Abl show that the N-terminal myristoyl modification of c-Abl 1b binds to the kinase domain and induces conformational changes that allow the SH2 and SH3 domains to dock onto it. Autoinhibited c-Abl forms an assembly that is strikingly similar to that of inactive Src kinases but with specific differences that explain the differential ability of the drug STI-571/Gleevec/imatinib (STI-571) to inhibit the catalytic activity of Abl, but not that of c-Src.
-===Structural basis for the auto-inhibition of c-Abl tyrosine kinase===
+Structural basis for the autoinhibition of c-Abl tyrosine kinase.,Nagar B, Hantschel O, Young MA, Scheffzek K, Veach D, Bornmann W, Clarkson B, Superti-Furga G, Kuriyan J Cell. 2003 Mar 21;112(6):859-71. PMID:12654251<ref>PMID:12654251</ref>
-{{ABSTRACT_PUBMED_12654251}}
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-==About this Structure==
+<div class="pdbe-citations 1opk" style="background-color:#fffaf0;"></div>
-[[1opk]] is a 1 chain structure of [[Proto-oncogene tyrosine-protein kinase]] with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OPK OCA].
 ==See Also==
-*[[Proto-oncogene tyrosine-protein kinase|Proto-oncogene tyrosine-protein kinase]]
+*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:012654251</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
 [[Category: Mus musculus]]
-[[Category: Transferase]]
+[[Category: Bornmann W]]
-[[Category: Bornmann, W.]]
+[[Category: Clarkson B]]
-[[Category: Clarkson, B.]]
+[[Category: Hantschel O]]
-[[Category: Hantschel, O.]]
+[[Category: Kuriyan J]]
-[[Category: Kuriyan, J.]]
+[[Category: Nagar B]]
-[[Category: Nagar, B.]]
+[[Category: Scheffzek K]]
-[[Category: Scheffzek, K.]]
+[[Category: Superti-Furga G]]
-[[Category: Superti-Furga, G.]]
+[[Category: Veach D]]
-[[Category: Veach, D.]]
+[[Category: Young MA]]
-[[Category: Young, M A.]]
-[[Category: Transferase]]