View source for 5mes


==MCL1 FAB COMPLEX IN COMPLEX WITH COMPOUND 29==
<StructureSection load='5mes' size='340' side='right'caption='[[5mes]], [[Resolution|resolution]] 2.24&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5mes]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MES OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MES FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.24&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7LT:(5~{R},13~{S},17~{S})-5-[[4-CHLORANYL-3-(2-PHENYLETHYL)PHENYL]METHYL]-13-[(4-CHLOROPHENYL)METHYL]-8-METHYL-1,4,8,12,16-PENTAZATRICYCLO[15.8.1.0^{20,25}]HEXACOSA-20(25),21,23-TRIENE-3,7,15,26-TETRONE'>7LT</scene></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=5mes FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mes OCA], [https://pdbe.org/5mes PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mes RCSB], [https://www.ebi.ac.uk/pdbsum/5mes PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mes ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MCL1_MOUSE MCL1_MOUSE] 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.[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 ==
Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 muM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a beta-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is a &lt;3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 muM and Bcl-xL at &gt;99 muM, and induces cleaved caspase-3 in MV4-11 cells with an IC50 of 3 muM after 6 h.

Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors.,Johannes JW, Bates S, Beigie C, Belmonte MA, Breen J, Cao S, Centrella PA, Clark MA, Cuozzo JW, Dumelin CE, Ferguson AD, Habeshian S, Hargreaves D, Joubran C, Kazmirski S, Keefe AD, Lamb ML, Lan H, Li Y, Ma H, Mlynarski S, Packer MJ, Rawlins PB, Robbins DW, Shen H, Sigel EA, Soutter HH, Su N, Troast DM, Wang H, Wickson KF, Wu C, Zhang Y, Zhao Q, Zheng X, Hird AW ACS Med Chem Lett. 2016 Dec 27;8(2):239-244. doi: 10.1021/acsmedchemlett.6b00464., eCollection 2017 Feb 9. PMID:28197319<ref>PMID:28197319</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5mes" style="background-color:#fffaf0;"></div>

==See Also==
*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Hargreaves D]]