4zbi

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==Mcl-1 complexed with small molecules==
==Mcl-1 complexed with small molecules==
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<StructureSection load='4zbi' size='340' side='right' caption='[[4zbi]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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<StructureSection load='4zbi' size='340' side='right'caption='[[4zbi]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4zbi]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZBI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZBI FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4zbi]] is a 12 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=4ZBI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZBI FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4M6:1-[3-(NAPHTHALEN-1-YLOXY)PROPYL]-5,6-DIHYDRO-4H-PYRROLO[3,2,1-IJ]QUINOLINE-2-CARBOXYLIC+ACID'>4M6</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zbf|4zbf]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4M6:1-[3-(NAPHTHALEN-1-YLOXY)PROPYL]-5,6-DIHYDRO-4H-PYRROLO[3,2,1-IJ]QUINOLINE-2-CARBOXYLIC+ACID'>4M6</scene></td></tr>
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<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=4zbi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zbi OCA], [http://pdbe.org/4zbi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zbi RCSB], [http://www.ebi.ac.uk/pdbsum/4zbi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zbi ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4zbi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zbi OCA], [https://pdbe.org/4zbi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zbi RCSB], [https://www.ebi.ac.uk/pdbsum/4zbi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zbi ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.
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Discovery of Tricyclic Indoles That Potently Inhibit Mcl-1 Using Fragment-Based Methods and Structure-Based Design.,Burke JP, Bian Z, Shaw S, Zhao B, Goodwin CM, Belmar J, Browning CF, Vigil D, Friberg A, Camper DV, Rossanese OW, Lee T, Olejniczak ET, Fesik SW J Med Chem. 2015 Apr 17. PMID:25844895<ref>PMID:25844895</ref>
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==See Also==
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*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4zbi" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Zhao, B]]
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[[Category: Homo sapiens]]
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[[Category: Complex]]
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[[Category: Large Structures]]
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[[Category: Inhibitor]]
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[[Category: Zhao B]]

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Mcl-1 complexed with small molecules

PDB ID 4zbi

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