8av9
From Proteopedia
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8av9]] 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=8AV9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AV9 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8av9]] 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=8AV9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AV9 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VF8:(3R,6R,7S,8E,11S,12R,22S)-6-chloro-7-methoxy-11,12-dimethyl-13,13-dioxo-spiro[20-oxa-13-gamma6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1-tetralin]-15-one'>VF8</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.99Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VF8:(3R,6R,7S,8E,11S,12R,22S)-6-chloro-7-methoxy-11,12-dimethyl-13,13-dioxo-spiro[20-oxa-13-gamma6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1-tetralin]-15-one'>VF8</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=8av9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8av9 OCA], [https://pdbe.org/8av9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8av9 RCSB], [https://www.ebi.ac.uk/pdbsum/8av9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8av9 ProSAT]</span></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=8av9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8av9 OCA], [https://pdbe.org/8av9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8av9 RCSB], [https://www.ebi.ac.uk/pdbsum/8av9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8av9 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[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> | [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 == | ||
| - | The structure-based design of small-molecule inhibitors targeting protein-protein interactions (PPIs) remains a huge challenge as the drug must bind typically wide and shallow protein sites. A PPI target of high interest for hematological cancer therapy is myeloid cell leukemia 1 (Mcl-1), a prosurvival guardian protein from the Bcl-2 family. Despite being previously considered undruggable, seven small-molecule Mcl-1 inhibitors have recently entered clinical trials. Here, we report the crystal structure of the clinical-stage inhibitor AMG-176 bound to Mcl-1 and analyze its interaction along with clinical inhibitors AZD5991 and S64315. Our X-ray data reveal high plasticity of Mcl-1 and a remarkable ligand-induced pocket deepening. Nuclear Magnetic Resonance (NMR)-based free ligand conformer analysis demonstrates that such unprecedented induced fit is uniquely achieved by designing highly rigid inhibitors, preorganized in their bioactive conformation. By elucidating key chemistry design principles, this work provides a roadmap for targeting the largely untapped PPI class more successfully. | ||
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| - | Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1.,Hargreaves D, Carbajo RJ, Bodnarchuk MS, Embrey K, Rawlins PB, Packer M, Degorce SL, Hird AW, Johannes JW, Chiarparin E, Schade M Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2221967120. doi: , 10.1073/pnas.2221967120. Epub 2023 May 15. PMID:37186857<ref>PMID:37186857</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 8av9" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
INDUCED MYELOID LEUKEMIA CELL DIFFERENTIATION PROTEIN FABCOMPLEX IN COMPLEX WITH COMPOUND 1
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