6ggc: Difference between revisions

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 <StructureSection load='6ggc' size='340' side='right'caption='[[6ggc]], [[Resolution|resolution]] 1.24&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ggc]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GGC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GGC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ggc]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GGC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GGC FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EXN:[9-ethyl-7-(furan-2-yl)carbazol-3-yl]methyl-methyl-azanium'>EXN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TP53, P53 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ggc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ggc OCA], [http://pdbe.org/6ggc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ggc RCSB], [http://www.ebi.ac.uk/pdbsum/6ggc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ggc ProSAT]</span></td></tr>
 </table>
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 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. We have solved high-resolution crystal structures of several oncogenic mutants to investigate the structural basis of inactivation and provide information for designing drugs that may rescue inactivated mutants. We found a variety of structural consequences upon mutation: (i) the removal of an essential contact with DNA, (ii) creation of large, water-accessible crevices or hydrophobic internal cavities with no other structural changes but with a large loss of thermodynamic stability, (iii) distortion of the DNA-binding surface, and (iv) alterations to surfaces not directly involved in DNA binding but involved in domain-domain interactions on binding as a tetramer. These findings explain differences in functional properties and associated phenotypes (e.g., temperature sensitivity). Some mutants have the potential of being rescued by a generic stabilizing drug. In addition, a mutation-induced crevice is a potential target site for a mutant-selective stabilizing drug.
+Aim: The p53 cancer mutation Y220C creates a conformationally unstable protein with a unique elongated surface crevice that can be targeted by molecular chaperones. We report the structure-guided optimization of the carbazole-based stabilizer PK083. Materials &amp; methods: Biophysical, cellular and x-ray crystallographic techniques have been employed to elucidate the mode of action of the carbazole scaffolds. Results: Targeting an unoccupied subsite of the surface crevice with heterocycle-substituted PK083 analogs resulted in a 70-fold affinity increase to single-digit micromolar levels, increased thermal stability and decreased rate of aggregation of the mutant protein. PK9318, one of the most potent binders, restored p53 signaling in the liver cancer cell line HUH-7 with homozygous Y220C mutation. Conclusion: The p53-Y220C mutant is an excellent paradigm for the development of mutant p53 rescue drugs via protein stabilization. Similar rescue strategies may be applicable to other cavity-creating p53 cancer mutations.
-Structural basis for understanding oncogenic p53 mutations and designing rescue drugs.,Joerger AC, Ang HC, Fersht AR Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15056-61. Epub 2006 Oct 2. PMID:17015838<ref>PMID:17015838</ref>
+A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C.,Bauer MR, Jones RN, Tareque RK, Springett B, Dingler FA, Verduci L, Patel KJ, Fersht AR, Joerger AC, Spencer J Future Med Chem. 2019 Oct;11(19):2491-2504. doi: 10.4155/fmc-2019-0181. PMID:31633398<ref>PMID:31633398</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Joerger, A C]]