4oq6: Difference between revisions
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==Crystal Structure of Human MCL-1 Bound to Inhibitor 4-hydroxy-4'-propylbiphenyl-3-carboxylic acid== | |||
<StructureSection load='4oq6' size='340' side='right' caption='[[4oq6]], [[Resolution|resolution]] 1.81Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4oq6]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OQ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OQ6 FirstGlance]. <br> | |||
==Function== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2UV:4-HYDROXY-4-PROPYLBIPHENYL-3-CARBOXYLIC+ACID'>2UV</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4oq5|4oq5]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MCL1, BCL2L3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4oq6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oq6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4oq6 RCSB], [http://www.ebi.ac.uk/pdbsum/4oq6 PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref> | [[http://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Apoptosis is regulated by the BCL-2 family of proteins, which is comprised of both pro-death and pro-survival members. Evasion of apoptosis is a hallmark of malignant cells. One way in which cancer cells achieve this evasion is thru overexpression of the pro-survival members of the BCL-2 family. Overexpression of MCL-1, a pro-survival protein, has been shown to be a resistance factor for Navitoclax, a potent inhibitor of BCL-2 and BCL-XL. Here we describe the use of fragment screening methods and structural biology to drive the discovery of novel MCL-1 inhibitors from two distinct structural classes. Specifically, cores derived from a biphenyl sulfonamide and salicylic acid were uncovered in an NMR-based fragment screen and elaborated using high throughput analog synthesis. This culminated in the discovery of selective and potent inhibitors of MCL-1 that may serve as promising leads for medicinal chemistry optimization efforts. | |||
Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein.,Petros AM, Swann SL, Song D, Swinger K, Park C, Zhang H, Wendt MD, Kunzer AR, Souers AJ, Sun C Bioorg Med Chem Lett. 2014 Mar 15;24(6):1484-8. doi: 10.1016/j.bmcl.2014.02.010. , Epub 2014 Feb 14. PMID:24582986<ref>PMID:24582986</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
[[Category: Kunzer, A R | == References == | ||
[[Category: Park, C | <references/> | ||
[[Category: Petros, A M | __TOC__ | ||
[[Category: Song, D | </StructureSection> | ||
[[Category: Souers, A J | [[Category: Human]] | ||
[[Category: Sun, C | [[Category: Kunzer, A R]] | ||
[[Category: Swann, S L | [[Category: Park, C]] | ||
[[Category: Swinger, K | [[Category: Petros, A M]] | ||
[[Category: Wendt, M D | [[Category: Song, D]] | ||
[[Category: Zhang, H | [[Category: Souers, A J]] | ||
[[Category: Sun, C]] | |||
[[Category: Swann, S L]] | |||
[[Category: Swinger, K]] | |||
[[Category: Wendt, M D]] | |||
[[Category: Zhang, H]] | |||
[[Category: Apoptosis-inhibitor complex]] | [[Category: Apoptosis-inhibitor complex]] | ||
