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| | ==Mcl-1 complexed with small molecule inhibitor== | | ==Mcl-1 complexed with small molecule inhibitor== |
| - | <StructureSection load='5fdr' size='340' side='right' caption='[[5fdr]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='5fdr' size='340' side='right'caption='[[5fdr]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5fdr]] 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=5FDR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FDR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5fdr]] 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=5FDR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FDR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5X3:5-[[6-CHLORANYL-3-[3-(4-CHLORANYL-3,5-DIMETHYL-PHENOXY)PROPYL]-7-(3,5-DIMETHYL-1~{H}-PYRAZOL-4-YL)-1~{H}-INDOL-2-YL]CARBONYLSULFAMOYL]FURAN-2-CARBOXYLIC+ACID'>5X3</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]] 2.6Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hw2|4hw2]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5X3:5-[[6-CHLORANYL-3-[3-(4-CHLORANYL-3,5-DIMETHYL-PHENOXY)PROPYL]-7-(3,5-DIMETHYL-1~{H}-PYRAZOL-4-YL)-1~{H}-INDOL-2-YL]CARBONYLSULFAMOYL]FURAN-2-CARBOXYLIC+ACID'>5X3</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5fdr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fdr OCA], [https://pdbe.org/5fdr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fdr RCSB], [https://www.ebi.ac.uk/pdbsum/5fdr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fdr ProSAT]</span></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=5fdr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fdr OCA], [http://pdbe.org/5fdr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fdr RCSB], [http://www.ebi.ac.uk/pdbsum/5fdr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fdr 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 5fdr" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5fdr" 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: Zhao, B]] | + | [[Category: Large Structures]] |
| - | [[Category: Apoptosis-apoptosis inhibitor complex]] | + | [[Category: Zhao B]] |
| - | [[Category: Inhibitor]]
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| - | [[Category: Mcl-1]]
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| 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) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.
Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.,Pelz NF, Bian Z, Zhao B, Shaw S, Tarr JC, Belmar J, Gregg C, Camper DV, Goodwin CM, Arnold AL, Sensintaffar JL, Friberg A, Rossanese OW, Lee T, Olejniczak ET, Fesik SW J Med Chem. 2016 Feb 24. PMID:26878343[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
- ↑ Pelz NF, Bian Z, Zhao B, Shaw S, Tarr JC, Belmar J, Gregg C, Camper DV, Goodwin CM, Arnold AL, Sensintaffar JL, Friberg A, Rossanese OW, Lee T, Olejniczak ET, Fesik SW. Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods. J Med Chem. 2016 Feb 24. PMID:26878343 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01660
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