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6vaj
From Proteopedia
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(New page: '''Unreleased structure''' The entry 6vaj is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal Structure Analysis of human PIN1== | |
| + | <StructureSection load='6vaj' size='340' side='right'caption='[[6vaj]], [[Resolution|resolution]] 1.42Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6vaj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VAJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VAJ 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]] 1.42Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=QT7:2-chloro-N-(2,2-dimethylpropyl)-N-[(3R)-1,1-dioxo-1lambda~6~-thiolan-3-yl]acetamide'>QT7</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6vaj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vaj OCA], [https://pdbe.org/6vaj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vaj RCSB], [https://www.ebi.ac.uk/pdbsum/6vaj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vaj ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/PIN1_HUMAN PIN1_HUMAN] Essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Catalyzes pSer/Thr-Pro cis/trans isomerizations. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation.<ref>PMID:15664191</ref> <ref>PMID:16644721</ref> <ref>PMID:21497122</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target. | ||
| - | + | Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo.,Dubiella C, Pinch BJ, Koikawa K, Zaidman D, Poon E, Manz TD, Nabet B, He S, Resnick E, Rogel A, Langer EM, Daniel CJ, Seo HS, Chen Y, Adelmant G, Sharifzadeh S, Ficarro SB, Jamin Y, Martins da Costa B, Zimmerman MW, Lian X, Kibe S, Kozono S, Doctor ZM, Browne CM, Yang A, Stoler-Barak L, Shah RB, Vangos NE, Geffken EA, Oren R, Koide E, Sidi S, Shulman Z, Wang C, Marto JA, Dhe-Paganon S, Look T, Zhou XZ, Lu KP, Sears RC, Chesler L, Gray NS, London N Nat Chem Biol. 2021 May 10. pii: 10.1038/s41589-021-00786-7. doi:, 10.1038/s41589-021-00786-7. PMID:33972797<ref>PMID:33972797</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6vaj" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Peptidyl-prolyl cis-trans isomerase 3D structures|Peptidyl-prolyl cis-trans isomerase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Dhe-Paganon S]] | ||
| + | [[Category: Seo H-S]] | ||
Current revision
Crystal Structure Analysis of human PIN1
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