7b4h: Difference between revisions
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==Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Human wild-type p53DBD bound to DNA and MQ: wt-DNA-MQ (III)== | |||
<StructureSection load='7b4h' size='340' side='right'caption='[[7b4h]], [[Resolution|resolution]] 1.39Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7b4h]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7B4H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B4H 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]] 1.39Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=QN8:(2~{R})-2-methyl-1-azabicyclo[2.2.2]octan-3-one'>QN8</scene>, <scene name='pdbligand=QNN:(2~{S})-2-methyl-1-azabicyclo[2.2.2]octan-3-one'>QNN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7b4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b4h OCA], [https://pdbe.org/7b4h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b4h RCSB], [https://www.ebi.ac.uk/pdbsum/7b4h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b4h ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1(MET)) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins. | |||
Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ).,Degtjarik O, Golovenko D, Diskin-Posner Y, Abrahmsen L, Rozenberg H, Shakked Z Nat Commun. 2021 Dec 3;12(1):7057. doi: 10.1038/s41467-021-27142-6. PMID:34862374<ref>PMID:34862374</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Diskin-Posner | <div class="pdbe-citations 7b4h" style="background-color:#fffaf0;"></div> | ||
[[Category: Rozenberg | |||
[[Category: Shakked | ==See Also== | ||
*[[P53 3D structures|P53 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Degtjarik O]] | |||
[[Category: Diskin-Posner Y]] | |||
[[Category: Rozenberg H]] | |||
[[Category: Shakked Z]] | |||
Latest revision as of 11:35, 17 October 2024
Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Human wild-type p53DBD bound to DNA and MQ: wt-DNA-MQ (III)Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Human wild-type p53DBD bound to DNA and MQ: wt-DNA-MQ (III)
Structural highlights
Publication Abstract from PubMedIn response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1(MET)) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins. Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ).,Degtjarik O, Golovenko D, Diskin-Posner Y, Abrahmsen L, Rozenberg H, Shakked Z Nat Commun. 2021 Dec 3;12(1):7057. doi: 10.1038/s41467-021-27142-6. PMID:34862374[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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