Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes

Kallen, Joerg; Goepfert, A.; Blechschmidt, Anke; Izaac, Aude; Geiser, Martin; Tavares, Gisele; Ramage, Paul; Furet, Pascal; Masuya, Keiichi; Lisztwan, Joanna

doi:10.1074/jbc.m809096200

Cited by 72 publications

(96 citation statements)

References 35 publications

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“…Several peptides, small molecules and peptidomimetics have been identified as inhibitors of this interaction between p53 and MDM2/ MDMX. 17,24,[28][29][30][31][32][33][34][35][36][37] The crystal structure of nutlin complexed to MDM2, PDB code 1RV1, 28 has been resolved at 2.3 Å. It shows (Fig.…”

Section: Resultsmentioning

confidence: 99%

Differential binding of p53 and nutlin to MDM2 and MDMX: Computational studies

Joseph

Madhumalar²,

Brown³

et al. 2010

Cell Cycle

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Section: Resultsmentioning

confidence: 99%

Differential binding of p53 and nutlin to MDM2 and MDMX: Computational studies

Joseph

Madhumalar²,

Brown³

et al. 2010

Cell Cycle

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“…Several new MDMX structures have been determined in complexes with a single-domain antibody (PDB ID code 2VYR) (50), peptidomimetic inhibitors (PDB ID codes 3FE7 and 3FEA) (51), and pDI (PDB ID code 3FDO).…”

Section: Methodsmentioning

confidence: 99%

Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX

Pazgier

Liu

Zou

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

345

514

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The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53-a cellular process initiated by MDM2 and/or MDMX binding to the Nterminal transactivation domain of p53. MDM2 and MDMX in many tumors confer p53 inactivation and tumor survival, and are important molecular targets for anticancer therapy. We screened a duodecimal peptide phage library against site-specifically biotinylated p53-binding domains of human MDM2 and MDMX chemically synthesized via native chemical ligation, and identified several peptide inhibitors of the p53-MDM2/MDMX interactions. The most potent inhibitor (TSFAEYWNLLSP), termed PMI, bound to MDM2 and MDMX at low nanomolar affinities-approximately 2 orders of magnitude stronger than the wild-type p53 peptide of the same length (ETFSDLWKLLPE). We solved the crystal structures of synthetic MDM2 and MDMX, both in complex with PMI, at 1.6 Å resolution. Comparative structural analysis identified an extensive, tightened intramolecular H-bonding network in bound PMI that contributed to its conformational stability, thus enhanced binding to the 2 oncogenic proteins. Importantly, the C-terminal residue Pro of PMI induced formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53-bound MDM2 or MDMX. Our findings deciphered the structural basis for highaffinity peptide inhibition of p53 interactions with MDM2 and MDMX, shedding new light on structure-based rational design of different classes of p53 activators for potential therapeutic use.

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“…4A), inhibitors that were specifically designed or screened for MDM2 binding are generally much weaker inhibitors of p53-MDMX interaction (Popowicz et al 2008). More recent studies have elucidated the binding modes of p53-derived peptides (Czarna et al 2009;Pazgier et al 2009) and a chlorinated peptidomimetic (Kallen et al 2009) that bind to both MDM2 and MDMX with low nanomolar affinities, two to three orders of magnitude tighter than the native p53 peptide. This wealth of novel structural information, which also offers insights into the conformational plasticity within the binding pocket of MDMX, is an excellent starting point for the development of cross-selective MDM2/MDMX inhibitors for use in cancer therapy.…”

Section: Targeting the P53 Pathway: Mdm2 Mdmx Sirtuins And Beyondmentioning

confidence: 99%

The Tumor Suppressor p53: From Structures to Drug Discovery

Joerger

Fersht²

2010

Cold Spring Harbor Perspectives in Biology

291

280

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Even 30 years after its discovery, the tumor suppressor protein p53 is still somewhat of an enigma. p53's intimate and multifaceted role in the cell cycle is mirrored in its equally complex structural biology that is being unraveled only slowly. Here, we discuss key structural aspects of p53 function and its inactivation by oncogenic mutations. Concerted action of folded and intrinsically disordered domains of the highly dynamic p53 protein provides binding promiscuity and specificity, allowing p53 to process a myriad of cellular signals to maintain the integrity of the human genome. Importantly, progress in elucidating the structural biology of p53 and its partner proteins has opened various avenues for structure-guided rescue of p53 function in tumors. These emerging anticancer strategies include targeting mutant-specific lesions on the surface of destabilized cancer mutants with small molecules and selective inhibition of p53's degradative pathways.

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Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes

Cited by 72 publications

References 35 publications

Differential binding of p53 and nutlin to MDM2 and MDMX: Computational studies

Differential binding of p53 and nutlin to MDM2 and MDMX: Computational studies

Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX

The Tumor Suppressor p53: From Structures to Drug Discovery

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