6q96
HDM2 (17-111, WILD TYPE) COMPLEXED WITH COMPOUND 12 AT 1.8A; Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes
Structural highlights
DiseaseMDM2_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. FunctionMDM2_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 PubMedHdm2 (human MDM2) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53-Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial. Here, we report four new X-ray structures for Hdm2 and five new X-ray structures for HdmX complexes, involving different classes of synthetic compounds. We also reveal the key additive 18-crown-ether, which we have discovered to enable HdmX crystallization and show its stabilization of various Lys-residues. In addition, we report the previously unpublished details of X-ray structure determinations for eight further Hdm2 complexes, including the clinical trial compounds NVP-CGM097 and NVP-HDM201. An analysis of all compound binding modes reveals new and deepened insights into the possible adaptations and structural states of Hdm2 (e.g. flip of F55; flip of Y67; reorientation of H96) and HdmX (e.g. flip of H55; dimer induction), enabling key binding interactions for different compound classes. In order to make comparisons easier, we have used the same numbering for Hdm2 and HdmX. Taken together, these structural insights should prove useful for the design and optimization of further selective and/or dual Hdm2/HdmX inhibitors. Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes.,Kallen J, Izaac A, Chau S, Wirth E, Schoepfer J, Mah R, Schlapbach A, Stutz S, Vaupel A, Guagnano V, Masuya K, Stachyra TM, Salem B, Chene P, Gessier F, Holzer P, Furet P ChemMedChem. 2019 May 8. doi: 10.1002/cmdc.201900201. PMID:31066983[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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