View source for 6qxj


==Structure of MBP-Mcl-1 in complex with compound 6a==
<StructureSection load='6qxj' size='340' side='right'caption='[[6qxj]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6qxj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_O157:H7 Escherichia coli O157:H7] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QXJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QXJ 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]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=JKQ:(2~{R})-2-[[6-ethyl-5-(1~{H}-indol-5-yl)thieno[2,3-d]pyrimidin-4-yl]amino]propanoic+acid'>JKQ</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PRD_900001:alpha-maltose'>PRD_900001</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=6qxj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qxj OCA], [https://pdbe.org/6qxj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qxj RCSB], [https://www.ebi.ac.uk/pdbsum/6qxj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qxj ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MALE_ECOLI MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.[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 ==
Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.

Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity.,Szlavik Z, Ondi L, Csekei M, Paczal A, Szabo ZB, Radics G, Murray J, Davidson J, Chen I, Davis B, Hubbard RE, Pedder C, Dokurno P, Surgenor A, Smith J, Robertson A, LeToumelin-Braizat G, Cauquil N, Zarka M, Demarles D, Perron-Sierra F, Claperon A, Colland F, Geneste O, Kotschy A J Med Chem. 2019 Jul 24. doi: 10.1021/acs.jmedchem.9b00134. PMID:31339316<ref>PMID:31339316</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6qxj" style="background-color:#fffaf0;"></div>

==See Also==
*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]]
*[[Maltose-binding protein 3D structures|Maltose-binding protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli O157:H7]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cauquil N]]
[[Category: Chen I]]
[[Category: Csekei M]]
[[Category: Davidson J]]
[[Category: Davis B]]
[[Category: Demarles D]]
[[Category: Dokurno P]]
[[Category: Geneste O]]
[[Category: Hubbard RE]]
[[Category: Kotschy A]]
[[Category: LeToumelin-Braizat G]]
[[Category: Murray J]]
[[Category: Ondi L]]
[[Category: Paczal A]]
[[Category: Pedder C]]
[[Category: Perron-Sierra F]]
[[Category: Radics G]]
[[Category: Robertson A]]
[[Category: Smith J]]
[[Category: Surgenor AE]]
[[Category: Szabo ZB]]
[[Category: Szlavik Z]]
[[Category: Zarka M]]