3FEA

Crystal Structure of HdmX bound to the p53-peptidomimetic Ac-Phe-Met-Aib-Pmp-6-Cl-Trp-Glu-Ac3c-Leu-NH2 at 1.33A

Summary for 3FEA

• Entry DOI: 10.2210/pdb3fea/pdb
• Related: 3DAB 3FE7
• Descriptor: Mdm4 protein, p53-peptidomimetic Ac-Phe-Met-Aib-Pmp-6-Cl-Trp-Glu-Ac3c-Leu-NH2, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (4 entities in total)
• Functional Keywords: hdmx, hdm4, human mdm4, human mdmx, protein-protein interaction, p53, metal-binding, nucleus, polymorphism, zinc, zinc-finger, cell cycle
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: O15151
• Total number of polymer chains: 3
• Total formula weight: 13690.62

Authors

Kallen, J. (deposition date: 2008-11-28, release date: 2009-01-27, Last modification date: 2023-11-22)

Primary citation

Kallen, J.,Goepfert, A.,Blechschmidt, A.,Izaac, A.,Geiser, M.,Tavares, G.,Ramage, P.,Furet, P.,Masuya, K.,Lisztwan, J.
Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes
J.Biol.Chem., 284:8812-8821, 2009

PubMed Abstract: p53 tumor suppressor activity is negatively regulated through binding to the oncogenic proteins Hdm2 and HdmX. The p53 residues Leu(26), Trp(23), and Phe(19) are crucial to mediate these interactions. Inhibiting p53 binding to both Hdm2 and HdmX should be a promising clinical approach to reactivate p53 in the cancer setting, but previous studies have suggested that the discovery of dual Hdm2/HdmX inhibitors will be difficult. We have determined the crystal structures at 1.3 A of the N-terminal domain of HdmX bound to two p53 peptidomimetics without and with a 6-chlorine substituent on the indole (which binds in the same subpocket as Trp(23) of p53). The latter compound is the most potent peptide-based antagonist of the p53-Hdm2 interaction yet to be described. The x-ray structures revealed surprising conformational changes of the binding cleft of HdmX, including an "open conformation" of Tyr(99) and unexpected "cross-talk" between the Trp and Leu pockets. Notably, the 6-chloro p53 peptidomimetic bound with high affinity to both HdmX and Hdm2 (K(d) values of 36 and 7 nm, respectively). Our results suggest that the development of potent dual inhibitors for HdmX and Hdm2 should be feasible. They also reveal possible conformational states of HdmX, which should lead to a better prediction of its interactions with potential biological partners.

PubMed: 19153082
DOI: 10.1074/jbc.M809096200

Experimental method

X-RAY DIFFRACTION (1.33 Å)