6qgd: Difference between revisions
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<StructureSection load='6qgd' size='340' side='right'caption='[[6qgd]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='6qgd' size='340' side='right'caption='[[6qgd]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6qgd]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QGD OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6qgd]] 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=6QGD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QGD FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=J1N:2-[(6-ethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)amino]-3-oxidanyl-propanoic+acid'>J1N</scene>, <scene name='pdbligand= | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</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=J1N:2-[(6-ethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)amino]-3-oxidanyl-propanoic+acid'>J1N</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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6qgd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qgd OCA], [https://pdbe.org/6qgd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qgd RCSB], [https://www.ebi.ac.uk/pdbsum/6qgd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qgd ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == 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 == | |||
We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using (1)H and (15)N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a K (d) of 40 muM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization. | |||
Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1.,Murray JB, Davidson J, Chen I, Davis B, Dokurno P, Graham CJ, Harris R, Jordan A, Matassova N, Pedder C, Ray S, Roughley SD, Smith J, Walmsley C, Wang Y, Whitehead N, Williamson DS, Casara P, Le Diguarher T, Hickman J, Stark J, Kotschy A, Geneste O, Hubbard RE ACS Omega. 2019 May 23;4(5):8892-8906. doi: 10.1021/acsomega.9b00611. eCollection , 2019 May 31. PMID:31459977<ref>PMID:31459977</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6qgd" 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__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Escherichia coli O157:H7]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Casara | [[Category: Casara P]] | ||
[[Category: Chen | [[Category: Chen I]] | ||
[[Category: Davidson | [[Category: Davidson J]] | ||
[[Category: Davis | [[Category: Davis B]] | ||
[[Category: Dokurno P]] | |||
[[Category: Dokurno | [[Category: Geneste O]] | ||
[[Category: Geneste | [[Category: Graham CJ]] | ||
[[Category: Graham | [[Category: Harris R]] | ||
[[Category: Harris | [[Category: Hickman J]] | ||
[[Category: Hickman | [[Category: Hubbard RE]] | ||
[[Category: Hubbard | [[Category: Jordan AM]] | ||
[[Category: Jordan | [[Category: Kotschy A]] | ||
[[Category: Kotschy | [[Category: Le Diguarher T]] | ||
[[Category: Matassova | [[Category: Matassova N]] | ||
[[Category: Murray | [[Category: Murray J]] | ||
[[Category: Pedder | [[Category: Pedder C]] | ||
[[Category: Ray | [[Category: Ray S]] | ||
[[Category: Roughley | [[Category: Roughley S]] | ||
[[Category: Smith | [[Category: Smith J]] | ||
[[Category: Stark | [[Category: Stark J]] | ||
[[Category: Walmsley | [[Category: Walmsley C]] | ||
[[Category: Wang | [[Category: Wang Y]] | ||
[[Category: Whitehead | [[Category: Whitehead N]] | ||
[[Category: Williamson | [[Category: Williamson DS]] | ||