7dt2: Difference between revisions

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<StructureSection load='7dt2' size='340' side='right'caption='[[7dt2]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
<StructureSection load='7dt2' size='340' side='right'caption='[[7dt2]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7dt2]] is a 2 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=7DT2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DT2 FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DT2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DT2 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]] 2.3&#8491;</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]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HJ9:[4-[5-[5-(dimethylcarbamoyl)pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-methanoyl-5-methoxy-phenyl]boronic+acid'>HJ9</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HJ9:[4-[5-[5-(dimethylcarbamoyl)pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-methanoyl-5-methoxy-phenyl]boronic+acid'>HJ9</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=7dt2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dt2 OCA], [https://pdbe.org/7dt2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dt2 RCSB], [https://www.ebi.ac.uk/pdbsum/7dt2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dt2 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=7dt2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dt2 OCA], [https://pdbe.org/7dt2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dt2 RCSB], [https://www.ebi.ac.uk/pdbsum/7dt2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dt2 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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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Anantharajan J]]
[[Category: Anantharajan J]]
[[Category: Baburajendran N]]
[[Category: Baburajendran N]]

Latest revision as of 09:13, 21 November 2024

Strategic design of catalytic lysine-targeting reversible covalent BCR-ABL InhibitorsStrategic design of catalytic lysine-targeting reversible covalent BCR-ABL Inhibitors

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Targeted covalent inhibitors have re-emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid (CBA) warhead, we report the structure-based design of BCR-ABL inhibitors via reversible covalent targeting of the catalytic lysine with improved potency against both wild-type and mutant ABL kinases, especially ABLT315I bearing the gatekeeper residue mutation. We show the evolutionarily conserved lysine can be targeted selectively, and the selectivity depends largely on molecular recognition of the non-covalent pharmacophore in this class of inhibitors, probably due to the moderate reactivity of the warhead. We report the first co-crystal structures of covalent inhibitor-ABL kinase domain complexes, providing insights into the interaction of this warhead with the catalytic lysine. We also employed label-free mass spectrometry to evaluate off-targets of our compounds at proteome-wide level in different mammalian cells.

Strategic Design of Catalytic Lysine-Targeting Reversible Covalent BCR-ABL Inhibitors.,Quach D, Tang G, Anantharajan J, Baburajendran N, Poulsen A, Wee J, Retna P, Li R, Liu B, Tee D, Kwek P, Joy J, Yang WQ, Zhang CJ, Foo K, Keller T, Yao SQ Angew Chem Int Ed Engl. 2021 May 19. doi: 10.1002/anie.202105383. PMID:34008286[1]

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

See Also

References

  1. ↑ Quach D, Tang G, Anantharajan J, Baburajendran N, Poulsen A, Wee J, Retna P, Li R, Liu B, Tee D, Kwek P, Joy J, Yang WQ, Zhang CJ, Foo K, Keller T, Yao SQ. Strategic Design of Catalytic Lysine-Targeting Reversible Covalent BCR-ABL Inhibitors. Angew Chem Int Ed Engl. 2021 May 19. doi: 10.1002/anie.202105383. PMID:34008286 doi:http://dx.doi.org/10.1002/anie.202105383

7dt2, resolution 2.30Å

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