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| | <StructureSection load='6bw2' size='340' side='right'caption='[[6bw2]], [[Resolution|resolution]] 2.75Å' scene=''> | | <StructureSection load='6bw2' size='340' side='right'caption='[[6bw2]], [[Resolution|resolution]] 2.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6bw2]] is a 4 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=6BW2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BW2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6bw2]] is a 4 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=6BW2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BW2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ECY:3-({11-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl}methyl)benzoic+acid'>ECY</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]] 2.75Å</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=ECY:3-({11-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl}methyl)benzoic+acid'>ECY</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=6bw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bw2 OCA], [http://pdbe.org/6bw2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bw2 RCSB], [http://www.ebi.ac.uk/pdbsum/6bw2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bw2 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=6bw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bw2 OCA], [https://pdbe.org/6bw2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bw2 RCSB], [https://www.ebi.ac.uk/pdbsum/6bw2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bw2 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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Zhao, B]] | + | [[Category: Zhao B]] |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Cancer]]
| + | |
| - | [[Category: Drug discovery]]
| + | |
| - | [[Category: Mcl-1 inhibitor]]
| + | |
| - | [[Category: Structure-based design]]
| + | |
| 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
Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1 sensitive cells. Thus, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.
Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors Using Structure-Based Design.,Shaw S, Bian Z, Zhao B, Tarr JC, Veerasamy N, Jeon K, Belmar J, Arnold AL, Fogarty SA, Perry E, Sensintaffar JL, Camper DV, Rossanese OW, Lee T, Olejniczak ET, Fesik SW J Med Chem. 2018 Jan 11. doi: 10.1021/acs.jmedchem.7b01155. PMID:29323899[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
- ↑ Shaw S, Bian Z, Zhao B, Tarr JC, Veerasamy N, Jeon K, Belmar J, Arnold AL, Fogarty SA, Perry E, Sensintaffar JL, Camper DV, Rossanese OW, Lee T, Olejniczak ET, Fesik SW. Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors Using Structure-Based Design. J Med Chem. 2018 Jan 11. doi: 10.1021/acs.jmedchem.7b01155. PMID:29323899 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01155
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