8g3t
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==MBP-Mcl1 in complex with ligand 12== | |
| + | <StructureSection load='8g3t' size='340' side='right'caption='[[8g3t]], [[Resolution|resolution]] 1.83Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8g3t]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Serratia_sp._FS14 Serratia sp. FS14]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G3T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G3T FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PRD_900001:alpha-maltose'>PRD_900001</scene>, <scene name='pdbligand=YLK:(1S,3aS,5R,16R,17S,19Z,21R,21aR)-6-chloro-20-fluoro-21-methoxy-16,17-dimethyl-2,3,3,3a,4,16,17,18,21,21a-decahydro-2H,6H,8H-15lambda~6~-spiro[10,12-etheno-15lambda~6~-furo[3,2-i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecine-7,1-naphthalene]-13,15,15(4H,14H)-trione'>YLK</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=8g3t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g3t OCA], [https://pdbe.org/8g3t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g3t RCSB], [https://www.ebi.ac.uk/pdbsum/8g3t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g3t ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/A0A4P1LXE0_SERSF A0A4P1LXE0_SERSF] Part of the ABC transporter complex MalEFGK involved in maltose/maltodextrin import. Binds maltose and higher maltodextrins.[RuleBase:RU365005][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 == | ||
| + | Avoidance of apoptosis is critical for the development and sustained growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins which is overexpressed in many cancers. Upregulation of Mcl-1 in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Therefore, pharmacological inhibition of Mcl-1 is regarded as an attractive approach to treating relapsed or refractory malignancies. Herein, we disclose the design, synthesis, optimization, and early preclinical evaluation of a potent and selective small-molecule inhibitor of Mcl-1. Our exploratory design tactics focused on structural modifications which improve the potency and physicochemical properties of the inhibitor while minimizing the risk of functional cardiotoxicity. Despite being in the "non-Lipinski" beyond-Rule-of-Five property space, the developed compound benefits from exquisite oral bioavailability in vivo and induces potent pharmacodynamic inhibition of Mcl-1 in a mouse xenograft model. | ||
| - | + | Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein-Protein Interaction Modulator with the Potential of Treating Hematological Malignancies.,Romanov-Michailidis F, Hsiao CC, Urner LM, Jerhaoui S, Surkyn M, Miller B, Vos A, Dominguez Blanco M, Bueters R, Vinken P, Bekkers M, Walker D, Pietrak B, Eyckmans W, Dores-Sousa JL, Joo Koo S, Lento W, Bauser M, Philippar U, Rombouts FJR J Med Chem. 2023 May 11;66(9):6122-6148. doi: 10.1021/acs.jmedchem.2c01953. Epub , 2023 Apr 28. PMID:37114951<ref>PMID:37114951</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8g3t" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Serratia sp. FS14]] | ||
| + | [[Category: Miller BR]] | ||
| + | [[Category: Shaffer P]] | ||
Revision as of 07:00, 18 May 2023
MBP-Mcl1 in complex with ligand 12
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