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  Transient Protein States in Designing Inhibitors of the MDM2-p53 Interaction

Bista, M., Wolf, S., Khoury, K., Kowalska, K., Huang, Y., Wrona, E., et al. (2013). Transient Protein States in Designing Inhibitors of the MDM2-p53 Interaction. STRUCTURE, 21(12), 2143-2151. doi:10.1016/j.str.2013.09.006.

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 Creators:
Bista, Michal1, Author              
Wolf, Siglinde1, Author              
Khoury, Kareem2, Author
Kowalska, Kaja1, Author              
Huang, Yijun2, Author
Wrona, Ewa2, Author
Arciniega, Marcelino3, Author              
Popowicz, Grzegorz M.1, Author              
Holak, Tad1, Author              
Domling, Alexander2, Author
Affiliations:
1Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565154              
2external, ou_persistent22              
3Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              

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Free keywords: SUPPRESSOR TRANSACTIVATION DOMAIN; CANCER-THERAPY; P53 PATHWAY; MULTICOMPONENT REACTIONS; MOLECULAR SIMULATIONS; P53-BINDING CLEFT; LEAD COMPOUNDS; MDMX; BINDING; ANTAGONISTS
 Abstract: Reactivation of p53 by release of the functional protein from its inhibition by MDM2 provides an efficient, nongenotoxic approach to a wide variety of cancers. We present the cocrystal structures of two complexes of MDM2 with inhibitors based on 6-chloroindole scaffolds. Both molecules bound to a distinct conformational state of MDM2 with nM-mu M affinities. In contrast to other structurally characterized antagonists, which mimic three amino acids of p53 (Phe19, Trp23, and Leu26), the compounds induced an additional hydrophobic pocket on the MDM2 surface and unveiled a four-point binding mode. The enlarged interaction interface of the inhibitors resulted in extension of small molecules binding toward the "lid" segment of MDM2 (residues 19-23) a nascent element that interferes with p53 binding. As supported by protein engineering and molecular dynamics studies, employing these unstable elements of MDM2 provides an efficient and yet unexplored alternative in development of MDM2-p53 association inhibitors.

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Language(s): eng - English
 Dates: 2013
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000328914900008
DOI: 10.1016/j.str.2013.09.006
 Degree: -

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Title: STRUCTURE
Source Genre: Journal
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Publ. Info: 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA : CELL PRESS
Pages: - Volume / Issue: 21 (12) Sequence Number: - Start / End Page: 2143 - 2151 Identifier: ISSN: 0969-2126