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| | <StructureSection load='6p3p' size='340' side='right'caption='[[6p3p]], [[Resolution|resolution]] 1.61Å' scene=''> | | <StructureSection load='6p3p' size='340' side='right'caption='[[6p3p]], [[Resolution|resolution]] 1.61Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6p3p]] is a 1 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=6P3P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P3P FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6p3p]] is a 1 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=6P3P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P3P FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NQJ:methyl+N-(5-{[2-chloro-5-(trifluoromethyl)phenyl]sulfamoyl}-4-methylthiophene-2-carbonyl)-D-phenylalaninate'>NQJ</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]] 1.61Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NQJ:methyl+N-(5-{[2-chloro-5-(trifluoromethyl)phenyl]sulfamoyl}-4-methylthiophene-2-carbonyl)-D-phenylalaninate'>NQJ</scene></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=6p3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p3p OCA], [http://pdbe.org/6p3p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p3p RCSB], [http://www.ebi.ac.uk/pdbsum/6p3p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p3p 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=6p3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p3p OCA], [https://pdbe.org/6p3p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p3p RCSB], [https://www.ebi.ac.uk/pdbsum/6p3p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p3p ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == 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> | + | [https://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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6p3p" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6p3p" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Follows, B]] | + | [[Category: Follows B]] |
| - | [[Category: Toms, A V]] | + | [[Category: Toms AV]] |
| - | [[Category: Apoptosis-apoptosis inhibitor complex]]
| + | |
| - | [[Category: Biaryl sulfonamide inhibitor]]
| + | |
| - | [[Category: Mcl-1]]
| + | |
| Structural highlights
Function
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.[1]
Publication Abstract from PubMed
Mcl-1 is an anti-apoptotic protein overexpressed in hematological malignancies and several human solid tumors. Small molecule inhibition of Mcl-1 would offer an effective therapy to Mcl-1 mediated resistance. Subsequently, it has been the target of extensive research in the pharmaceutical industry. The discovery of a novel class of Mcl-1 small molecule inhibitors is described beginning with a simple biaryl sulfonamide hit derived from a high through put screen. A medicinal chemistry effort aided by SBDD generated compounds capable of disrupting the Mcl-1/Bid protein-protein interaction in vitro. The crystal structure of the Mcl-1 bound ligand represents a unique binding mode to the BH3 binding pocket where binding affinity is achieved, in part, through a sulfonamide oxygen/Arg263 interaction. The work highlights the some of the key challenges in designing effective protein-protein inhibitors for the Bcl-2 class of proteins.
Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors.,Follows B, Fessler S, Baumeister T, Campbell AM, Zablocki MM, Li H, Gotur D, Wang Z, Zheng X, Molz L, Nguyen C, Herbertz T, Wang L, Bair K Bioorg Med Chem Lett. 2019 Jun 11. pii: S0960-894X(19)30375-0. doi:, 10.1016/j.bmcl.2019.06.008. PMID:31235261[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bingle CD, Craig RW, Swales BM, Singleton V, Zhou P, Whyte MK. Exon skipping in Mcl-1 results in a bcl-2 homology domain 3 only gene product that promotes cell death. J Biol Chem. 2000 Jul 21;275(29):22136-46. PMID:10766760 doi:10.1074/jbc.M909572199
- ↑ Follows B, Fessler S, Baumeister T, Campbell AM, Zablocki MM, Li H, Gotur D, Wang Z, Zheng X, Molz L, Nguyen C, Herbertz T, Wang L, Bair K. Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors. Bioorg Med Chem Lett. 2019 Jun 11. pii: S0960-894X(19)30375-0. doi:, 10.1016/j.bmcl.2019.06.008. PMID:31235261 doi:http://dx.doi.org/10.1016/j.bmcl.2019.06.008
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