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<StructureSection load='7w7x' size='340' side='right'caption='[[7w7x]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='7w7x' size='340' side='right'caption='[[7w7x]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7w7x]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7W7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W7X FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7W7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W7X FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8DW:5-[5-(dimethylcarbamoyl)pyridin-3-yl]-3-(5-fluorosulfonyloxy-2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine'>8DW</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]] 2.0000093&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8DW:5-[5-(dimethylcarbamoyl)pyridin-3-yl]-3-(5-fluorosulfonyloxy-2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine'>8DW</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7w7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w7x OCA], [https://pdbe.org/7w7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w7x RCSB], [https://www.ebi.ac.uk/pdbsum/7w7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w7x 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=7w7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w7x OCA], [https://pdbe.org/7w7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w7x RCSB], [https://www.ebi.ac.uk/pdbsum/7w7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w7x ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
== Function ==
[[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] 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-153' 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. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 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.<ref>PMID:9037071</ref> <ref>PMID:9144171</ref> <ref>PMID:9461559</ref> <ref>PMID:10391250</ref> <ref>PMID:12379650</ref> <ref>PMID:11971963</ref> <ref>PMID:12531427</ref> <ref>PMID:12672821</ref> <ref>PMID:15556646</ref> <ref>PMID:15031292</ref> <ref>PMID:15886098</ref> <ref>PMID:15657060</ref> <ref>PMID:16943190</ref> <ref>PMID:16678104</ref> <ref>PMID:17306540</ref> <ref>PMID:17623672</ref> <ref>PMID:18328268</ref> <ref>PMID:18945674</ref> <ref>PMID:19891780</ref> <ref>PMID:20417104</ref> <ref>PMID:16424036</ref> <ref>PMID:20357770</ref> 
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Zhang ZM]]
[[Category: Zhang, Z M]]
[[Category: Zhu C]]
[[Category: Zhu, C]]
[[Category: Abl1]]
[[Category: Transferase]]

Latest revision as of 12:18, 17 October 2024

The crystal structure of human abl1 kinase domain in complex with ABL1-A11The crystal structure of human abl1 kinase domain in complex with ABL1-A11

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.0000093Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR-ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug-resistant ABL mutations. Among them, the salicylaldehyde-containing A5 is the first-ever reversible covalent ABL inhibitor that possessed time-dependent ABL inhibition with prolonged residence time and few cellular off-targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome.

Cell-Active, Reversible, and Irreversible Covalent Inhibitors that Selectively Target the Catalytic Lysine of BCR-ABL Kinase.,Chen P, Sun J, Zhu C, Tang G, Wang W, Xu M, Xiang M, Zhang C, Zhang ZM, Gao L, Yao SQ Angew Chem Int Ed Engl. 2022 Apr 19. doi: 10.1002/anie.202203878. PMID:35438229[1]

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

See Also

References

  1. ↑ Chen P, Sun J, Zhu C, Tang G, Wang W, Xu M, Xiang M, Zhang C, Zhang ZM, Gao L, Yao SQ. Cell-Active, Reversible, and Irreversible Covalent Inhibitors that Selectively Target the Catalytic Lysine of BCR-ABL Kinase. Angew Chem Int Ed Engl. 2022 Apr 19. doi: 10.1002/anie.202203878. PMID:35438229 doi:http://dx.doi.org/10.1002/anie.202203878

7w7x, resolution 2.00Å

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