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2xyn

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Revision as of 18:52, 1 February 2017

HUMAN ABL2 IN COMPLEX WITH AURORA KINASE INHIBITOR VX-680

Structural highlights

2xyn is a 3 chain structure with sequence from Human. This structure supersedes the now removed PDB entry 3nsv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Activity:	Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[ABL2_HUMAN] Non-receptor tyrosine-protein kinase that plays an ABL1-overlapping role in key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion and receptor endocytosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like MYH10 (involved in movement); CTTN (involved in signaling); or TUBA1 and TUBB (microtubule subunits). Binds directly F-actin and regulates actin cytoskeletal structure through its F-actin-bundling activity. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as CRK, CRKL, DOK1 or ARHGAP35. Adhesion-dependent phosphorylation of ARHGAP35 promotes its association with RASA1, resulting in recruitment of ARHGAP35 to the cell periphery where it inhibits RHO. Phosphorylates multiple receptor tyrosine kinases like PDGFRB and other substrates which are involved in endocytosis regulation such as RIN1. In brain, may regulate neurotransmission by phosphorylating proteins at the synapse. ABL2 acts also as a regulator of multiple pathological signaling cascades during infection. Pathogens can highjack ABL2 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

ABL2 (also known as ARG (ABL related gene)) is closely related to the well-studied Abelson kinase cABL. ABL2 is involved in human neoplastic diseases and is deregulated in solid tumors. Oncogenic gene translocations occur in acute leukemia. So far no structural information for ABL2 has been reported. To elucidate structural determinants for inhibitor interaction, we determined the cocrystal structure of ABL2 with the oncology drug imatinib. Interestingly, imatinib not only interacted with the ATP binding site of the inactive kinase but was also bound to the regulatory myristate binding site. This structure may therefore serve as a tool for the development of allosteric ABL inhibitors. In addition, we determined the structures of ABL2 in complex with VX-680 and with an ATP-mimetic type I inhibitor, which revealed an interesting position of the DFG motif intermediate between active and inactive conformations, that may also serve as a template for future inhibitor design.

Crystal Structures of ABL-Related Gene (ABL2) in Complex with Imatinib, Tozasertib (VX-680), and a Type I Inhibitor of the Triazole Carbothioamide Class.,Salah E, Ugochukwu E, Barr AJ, von Delft F, Knapp S, Elkins JM J Med Chem. 2011 Mar 18. PMID:21417343^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hu H, Bliss JM, Wang Y, Colicelli J. RIN1 is an ABL tyrosine kinase activator and a regulator of epithelial-cell adhesion and migration. Curr Biol. 2005 May 10;15(9):815-23. PMID:15886098 doi:10.1016/j.cub.2005.03.049
↑ Cao C, Li Y, Leng Y, Li P, Ma Q, Kufe D. Ubiquitination and degradation of the Arg tyrosine kinase is regulated by oxidative stress. Oncogene. 2005 Apr 7;24(15):2433-40. PMID:15735735 doi:10.1038/sj.onc.1208454
↑ Liu X, Huang W, Li C, Li P, Yuan J, Li X, Qiu XB, Ma Q, Cao C. Interaction between c-Abl and Arg tyrosine kinases and proteasome subunit PSMA7 regulates proteasome degradation. Mol Cell. 2006 May 5;22(3):317-27. PMID:16678104 doi:10.1016/j.molcel.2006.04.007
↑ Boyle SN, Michaud GA, Schweitzer B, Predki PF, Koleske AJ. A critical role for cortactin phosphorylation by Abl-family kinases in PDGF-induced dorsal-wave formation. Curr Biol. 2007 Mar 6;17(5):445-51. Epub 2007 Feb 15. PMID:17306540 doi:10.1016/j.cub.2007.01.057
↑ Yogalingam G, Pendergast AM. Abl kinases regulate autophagy by promoting the trafficking and function of lysosomal components. J Biol Chem. 2008 Dec 19;283(51):35941-53. doi: 10.1074/jbc.M804543200. Epub 2008, Oct 21. PMID:18945674 doi:10.1074/jbc.M804543200
↑ Salah E, Ugochukwu E, Barr AJ, von Delft F, Knapp S, Elkins JM. Crystal Structures of ABL-Related Gene (ABL2) in Complex with Imatinib, Tozasertib (VX-680), and a Type I Inhibitor of the Triazole Carbothioamide Class. J Med Chem. 2011 Mar 18. PMID:21417343 doi:10.1021/jm101506n

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2xyn"

@@ Line 1: / Line 1: @@
 ==HUMAN ABL2 IN COMPLEX WITH AURORA KINASE INHIBITOR VX-680==
 <StructureSection load='2xyn' size='340' side='right' caption='[[2xyn]], [[Resolution|resolution]] 2.81&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=VX6:CYCLOPROPANECARBOXYLIC+ACID+{4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE'>VX6</scene></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=2xyn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xyn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xyn RCSB], [http://www.ebi.ac.uk/pdbsum/2xyn 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=2xyn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xyn OCA], [http://pdbe.org/2xyn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xyn RCSB], [http://www.ebi.ac.uk/pdbsum/2xyn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xyn ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2xyn" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Tyrosine kinase|Tyrosine kinase]]
 == References ==
 <references/>

2xyn

From Proteopedia

Revision as of 18:52, 1 February 2017

HUMAN ABL2 IN COMPLEX WITH AURORA KINASE INHIBITOR VX-680

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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