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4zbf

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Revision as of 07:47, 10 May 2023

Mcl-1 complexed with small molecules

Structural highlights

4zbf is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 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.

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ 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. Discovery of Tricyclic Indoles That Potently Inhibit Mcl-1 Using Fragment-Based Methods and Structure-Based Design. J Med Chem. 2015 Apr 17. PMID:25844895 doi:http://dx.doi.org/10.1021/jm501984f

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4zbf"

Categories: Homo sapiens | Large Structures | Zhao B

@@ Line 3: / Line 3: @@
 <StructureSection load='4zbf' size='340' side='right'caption='[[4zbf]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4zbf]] is a 12 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=4ZBF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZBF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4zbf]] 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=4ZBF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZBF FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4M7:(1R)-7-[3-(NAPHTHALEN-1-YLOXY)PROPYL]-3,4-DIHYDRO-2H-[1,4]THIAZEPINO[2,3,4-HI]INDOLE-6-CARBOXYLIC+ACID+1-OXIDE'>4M7</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4M7:(1R)-7-[3-(NAPHTHALEN-1-YLOXY)PROPYL]-3,4-DIHYDRO-2H-[1,4]THIAZEPINO[2,3,4-HI]INDOLE-6-CARBOXYLIC+ACID+1-OXIDE'>4M7</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hw2|4hw2]], [[4zbi|4zbi]]</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=4zbf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zbf OCA], [https://pdbe.org/4zbf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zbf RCSB], [https://www.ebi.ac.uk/pdbsum/4zbf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zbf ProSAT]</span></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=4zbf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zbf OCA], [http://pdbe.org/4zbf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zbf RCSB], [http://www.ebi.ac.uk/pdbsum/4zbf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zbf ProSAT]</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>
+[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;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Zhao, B]]
+[[Category: Zhao B]]
-[[Category: Apoptosis-apoptosis inhibitor complex]]
-[[Category: Complex]]
-[[Category: Inhibitor]]

4zbf

From Proteopedia

Revision as of 07:47, 10 May 2023

Mcl-1 complexed with small molecules

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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