5oai

From Proteopedia

(Difference between revisions)

Revision as of 06:25, 17 April 2019

Structure of MDM2 with low molecular weight inhibitor

Structural highlights

5oai is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	MDM2 (HUMAN)
Activity:	RING-type E3 ubiquitin transferase, with EC number 2.3.2.27
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[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

[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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11]

Publication Abstract from PubMed

The p53 protein is engaged in the repair of DNA mutations and elimination of heavily damaged cells, providing anti-cancer protection. Dysregulation of p53 activity is a crucial step in carcinogenesis. This dysregulation is often caused by the overexpression of negative regulators of p53, among which MDM2 is the most prominent one. Antagonizing MDM2 with small molecules restores the activity of p53 in p53 wild-type (p53(wt) ) cells and thus provides positive outcomes in the treatment of p53(wt) cancers. Previously, we have reported the discovery of a panel of fluoro-substituted indole-based antagonists of MDM2. Here, we demonstrate the biological activity and stereoselectivity of the most active compound from this series. Both enantiomers of the esterified form of the compound, as well as its corresponding carboxylic acids, were found active in fluorescence polarization (FP) assay, nuclear magnetic resonance (NMR) and microscale thermophoresis (MST) assay, with Ki and KD values around 1 muM. From these four compounds, the esterified enantiomer (R)-5a was active in cells, which was evidenced by the increase of p53 levels, the induced expression of p53-target genes (CDKN1A and MDM2), the selective induction of cell cycle arrest and selective growth inhibition of p53(wt) U-2 OS and SJSA-1 compared to p53(del) SAOS-2 cells. The analysis of the crystal structure of human MDM2 in complex with the compound (R)-6a (carboxylic acid of the active (R)-5a compound) revealed the classical three-finger binding mode. Altogether, our data demonstrate the activity of the compound and provide the structural basis for further structure optimization. This article is protected by copyright. All rights reserved.

A fluorinated indole-based MDM2 antagonist selectively inhibits the growth of p53(wt) osteosarcoma cells.,Skalniak L, Twarda-Clapa A, Neochoritis CG, Surmiak E, Machula M, Wisniewska A, Labuzek B, Ali AM, Krzanik S, Dubin G, Groves M, Domling A, Holak TA FEBS J. 2019 Feb 4. doi: 10.1111/febs.14774. PMID:30715803^[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Girnita L, Girnita A, Larsson O. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8247-52. Epub 2003 Jun 23. PMID:12821780 doi:10.1073/pnas.1431613100
↑ Li M, Brooks CL, Kon N, Gu W. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell. 2004 Mar 26;13(6):879-86. PMID:15053880
↑ Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol. 2004 Jul;6(7):665-72. Epub 2004 Jun 13. PMID:15195100 doi:10.1038/ncb1147
↑ Sdek P, Ying H, Chang DL, Qiu W, Zheng H, Touitou R, Allday MJ, Xiao ZX. MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Mol Cell. 2005 Dec 9;20(5):699-708. PMID:16337594 doi:10.1016/j.molcel.2005.10.017
↑ Brady M, Vlatkovic N, Boyd MT. Regulation of p53 and MDM2 activity by MTBP. Mol Cell Biol. 2005 Jan;25(2):545-53. PMID:15632057 doi:25/2/545
↑ Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, Saville MK. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 2007 Feb 21;26(4):976-86. Epub 2007 Feb 8. PMID:17290220 doi:10.1038/sj.emboj.7601567
↑ Chen D, Zhang J, Li M, Rayburn ER, Wang H, Zhang R. RYBP stabilizes p53 by modulating MDM2. EMBO Rep. 2009 Feb;10(2):166-72. doi: 10.1038/embor.2008.231. Epub 2008 Dec 19. PMID:19098711 doi:10.1038/embor.2008.231
↑ Busso CS, Iwakuma T, Izumi T. Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway. Oncogene. 2009 Apr 2;28(13):1616-25. doi: 10.1038/onc.2009.5. Epub 2009 Feb 16. PMID:19219073 doi:10.1038/onc.2009.5
↑ Taira N, Yamamoto H, Yamaguchi T, Miki Y, Yoshida K. ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage. J Biol Chem. 2010 Feb 12;285(7):4909-19. doi: 10.1074/jbc.M109.042341. Epub 2009 , Dec 4. PMID:19965871 doi:10.1074/jbc.M109.042341
↑ Gilmore-Hebert M, Ramabhadran R, Stern DF. Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways. Mol Cancer Res. 2010 Oct;8(10):1388-98. doi: 10.1158/1541-7786.MCR-10-0042. Epub , 2010 Sep 21. PMID:20858735 doi:10.1158/1541-7786.MCR-10-0042
↑ Fu X, Yucer N, Liu S, Li M, Yi P, Mu JJ, Yang T, Chu J, Jung SY, O'Malley BW, Gu W, Qin J, Wang Y. RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4579-84. doi:, 10.1073/pnas.0912094107. Epub 2010 Feb 19. PMID:20173098 doi:10.1073/pnas.0912094107
↑ Skalniak L, Twarda-Clapa A, Neochoritis CG, Surmiak E, Machula M, Wisniewska A, Labuzek B, Ali AM, Krzanik S, Dubin G, Groves M, Domling A, Holak TA. A fluorinated indole-based MDM2 antagonist selectively inhibits the growth of p53(wt) osteosarcoma cells. FEBS J. 2019 Feb 4. doi: 10.1111/febs.14774. PMID:30715803 doi:http://dx.doi.org/10.1111/febs.14774

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5oai"

@@ Line 1: / Line 1: @@
 ==Structure of MDM2 with low molecular weight inhibitor==
-<StructureSection load='5oai' size='340' side='right' caption='[[5oai]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='5oai' size='340' side='right'caption='[[5oai]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5oai]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OAI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OAI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5oai]] is a 1 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=5OAI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OAI FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B5K:3-[(1~{R})-2-(~{tert}-butylamino)-1-[methanoyl-[[3,4,5-tris(fluoranyl)phenyl]methyl]amino]-2-oxidanylidene-ethyl]-6-chloranyl-1~{H}-indole-2-carboxylic+acid'>B5K</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MDM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RING-type_E3_ubiquitin_transferase RING-type E3 ubiquitin transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.27 2.3.2.27] </span></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=5oai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oai OCA], [http://pdbe.org/5oai PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5oai RCSB], [http://www.ebi.ac.uk/pdbsum/5oai PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5oai ProSAT]</span></td></tr>
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: RING-type E3 ubiquitin transferase]]
 [[Category: Domling, A]]

5oai

From Proteopedia

Revision as of 06:25, 17 April 2019

Structure of MDM2 with low molecular weight inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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