View source for 6vwc


==Crystal structure of Bcl-xL in complex with tetrahydroisoquinoline-pyridine based inhibitors==
<StructureSection load='6vwc' size='340' side='right'caption='[[6vwc]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6vwc]] 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=6VWC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VWC 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]] 1.604&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RQ7:6-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}-3-{1-[(pyridin-4-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic+acid'>RQ7</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=6vwc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vwc OCA], [https://pdbe.org/6vwc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vwc RCSB], [https://www.ebi.ac.uk/pdbsum/6vwc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vwc ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/B2CL1_HUMAN B2CL1_HUMAN] Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref>   Isoform Bcl-X(S) promotes apoptosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref> 
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== Publication Abstract from PubMed ==
Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp(3)-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL. A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program.

Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor.,Wang L, Doherty GA, Judd AS, Tao ZF, Hansen TM, Frey RR, Song X, Bruncko M, Kunzer AR, Wang X, Wendt MD, Flygare JA, Catron ND, Judge RA, Park CH, Shekhar S, Phillips DC, Nimmer P, Smith ML, Tahir SK, Xiao Y, Xue J, Zhang H, Le PN, Mitten MJ, Boghaert ER, Gao W, Kovar P, Choo EF, Diaz D, Fairbrother WJ, Elmore SW, Sampath D, Leverson JD, Souers AJ ACS Med Chem Lett. 2020 Mar 30;11(10):1829-1836. doi:, 10.1021/acsmedchemlett.9b00568. eCollection 2020 Oct 8. PMID:33062160<ref>PMID:33062160</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6vwc" style="background-color:#fffaf0;"></div>

==See Also==
*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Judd AS]]
[[Category: Judge RA]]