This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

4zbi

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 10:02, 10 March 2017

Mcl-1 complexed with small molecules

Structural highlights

4zbi is a 12 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4zbf
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 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

Categories: Zhao, B | Complex | Inhibitor

@@ Line 1: / Line 1: @@
 ==Mcl-1 complexed with small molecules==
 <StructureSection load='4zbi' size='340' side='right' caption='[[4zbi]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </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>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zbf|4zbf]]</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=4zbi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zbi OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4zbi RCSB], [http://www.ebi.ac.uk/pdbsum/4zbi PDBsum]</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=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>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4zbi" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4zbi

From Proteopedia

Revision as of 10:02, 10 March 2017

Mcl-1 complexed with small molecules

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox