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4zyc

From Proteopedia

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Revision as of 07:46, 18 May 2023

Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode: Hdm2 (MDM2) complexed with cpd5

Structural highlights

4zyc is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
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

Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogs. The X-ray structure revealed an unprecedented binding mode for p53-MDM2 inhibitors.

Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode.,Gessier F, Kallen J, Jacoby E, Chene P, Stachyra-Valat T, Ruetz S, Jeay S, Holzer P, Masuya K, Furet P Bioorg Med Chem Lett. 2015 Jun 23. pii: S0960-894X(15)00651-4. doi:, 10.1016/j.bmcl.2015.06.058. PMID:26141769^[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
↑ Gessier F, Kallen J, Jacoby E, Chene P, Stachyra-Valat T, Ruetz S, Jeay S, Holzer P, Masuya K, Furet P. Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode. Bioorg Med Chem Lett. 2015 Jun 23. pii: S0960-894X(15)00651-4. doi:, 10.1016/j.bmcl.2015.06.058. PMID:26141769 doi:http://dx.doi.org/10.1016/j.bmcl.2015.06.058

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4zyc"

Categories: Homo sapiens | Large Structures | Kallen J

@@ Line 1: / Line 1: @@
 ==Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode: Hdm2 (MDM2) complexed with cpd5==
-<StructureSection load='4zyc' size='340' side='right' caption='[[4zyc]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+<StructureSection load='4zyc' size='340' side='right'caption='[[4zyc]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4zyc]] is a 3 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=4ZYC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZYC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4zyc]] is a 3 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=4ZYC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZYC FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4SS:(S)-2-(2-((2H-TETRAZOL-5-YL)METHOXY)-4-METHYLPHENYL)-1-(4-CHLOROPHENYL)-6,7-DIETHOXY-1,2-DIHYDROISOQUINOLIN-3(4H)-ONE'>4SS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4SS:(S)-2-(2-((2H-TETRAZOL-5-YL)METHOXY)-4-METHYLPHENYL)-1-(4-CHLOROPHENYL)-6,7-DIETHOXY-1,2-DIHYDROISOQUINOLIN-3(4H)-ONE'>4SS</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">[[4dij|4dij]], [[4oq3|4oq3]]</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=4zyc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zyc OCA], [https://pdbe.org/4zyc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zyc RCSB], [https://www.ebi.ac.uk/pdbsum/4zyc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zyc ProSAT]</span></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='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=4zyc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zyc OCA], [http://pdbe.org/4zyc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zyc RCSB], [http://www.ebi.ac.uk/pdbsum/4zyc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zyc ProSAT]</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.
+[https://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>
+[https://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 ==
@@ Line 22: / Line 20: @@
 </div>
 <div class="pdbe-citations 4zyc" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[MDM2 3D structures|MDM2 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Kallen, J]]
+[[Category: Large Structures]]
-[[Category: Inhibitor complex]]
+[[Category: Kallen J]]
-[[Category: Ligase]]
-[[Category: Ppi with p53]]

4zyc

From Proteopedia

Revision as of 07:46, 18 May 2023

Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode: Hdm2 (MDM2) complexed with cpd5

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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