5hmh
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==HDM2 in complex with a 3,3-Disubstituted Piperidine== | |
| + | <StructureSection load='5hmh' size='340' side='right' caption='[[5hmh]], [[Resolution|resolution]] 1.79Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5hmh]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HMH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HMH FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=62R:4-[2-(4-{[(2R,3S)-2-PROPYL-1-{[4-(TRIFLUOROMETHYL)PYRIDIN-3-YL]CARBONYL}-3-{[5-(TRIFLUOROMETHYL)THIOPHEN-3-YL]OXY}PIPERIDIN-3-YL]CARBONYL}PIPERAZIN-1-YL)PHENOXY]BUTANOIC+ACID'>62R</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5hmk|5hmk]], [[5hmi|5hmi]]</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=5hmh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hmh OCA], [http://pdbe.org/5hmh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hmh RCSB], [http://www.ebi.ac.uk/pdbsum/5hmh PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.<ref>PMID:12821780</ref> <ref>PMID:15053880</ref> <ref>PMID:15195100</ref> <ref>PMID:16337594</ref> <ref>PMID:15632057</ref> <ref>PMID:17290220</ref> <ref>PMID:19098711</ref> <ref>PMID:19219073</ref> <ref>PMID:19965871</ref> <ref>PMID:20858735</ref> <ref>PMID:20173098</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described. | ||
| - | + | Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors.,Bogen SL, Pan W, Gibeau CR, Lahue BR, Ma Y, Nair LG, Seigel E, Shipps GW Jr, Tian Y, Wang Y, Lin Y, Liu M, Liu S, Mirza A, Wang X, Lipari P, Seidel-Dugan C, Hicklin DJ, Bishop WR, Rindgen D, Nomeir A, Prosise W, Reichert P, Scapin G, Strickland C, Doll RJ ACS Med Chem Lett. 2016 Jan 20;7(3):324-9. doi: 10.1021/acsmedchemlett.5b00472., eCollection 2016 Mar 10. PMID:26985323<ref>PMID:26985323</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| + | <div class="pdbe-citations 5hmh" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Scapin, G]] | [[Category: Scapin, G]] | ||
| + | [[Category: E3 ubiquitin-protein ligase]] | ||
| + | [[Category: Ligase-ligase inhibitor complex]] | ||
| + | [[Category: Oncology]] | ||
| + | [[Category: P53/tp53]] | ||
Revision as of 04:11, 12 May 2016
HDM2 in complex with a 3,3-Disubstituted Piperidine
| |||||||||||
