Retracted: Structural studies of antitumor compounds that target the RING domain of MDM2
[1]
- Center for Diagnostics and Therapeutics Georgia State University Atlanta Georgia USA, Department of Chemistry Georgia State University Atlanta Georgia USA
- Institute for Biomedical Sciences Georgia State University Atlanta Georgia USA
- Department of Chemistry Georgia State University Atlanta Georgia USA
- Department of Chemistry University of Alabama at Birmingham Birmingham Alabama USA
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy University of Houston Houston Texas USA, Drug Discovery Institute University of Houston Houston Texas USA
Abstract Mouse double minute 2 homolog (MDM2) is an E3 ubiquitin‐protein ligase that is involved in the transfer of ubiquitin to p53 and other protein substrates. The expression of MDM2 is elevated in cancer cells and inhibitors of MDM2 showed potent anticancer activities. Many inhibitors target the p53 binding domain of MDM2. However, inhibitors such as Inulanolide A and MA242 are found to bind the RING domain of MDM2 to block ubiquitin transfer. In this report, crystal structures of MDM2 RING domain in complex with Inulanolide A and MA242 were solved. These inhibitors primarily bind in a hydrophobic site centered at the sidechain of Tyr489 at the C‐terminus of MDM2 RING domain. The C‐terminus of MDM2 RING domain, especially residue Tyr489, is required for ubiquitin discharge induced by MDM2. The binding of these inhibitors at Tyr489 may interrupt interactions between the MDM2 RING domain and the E2‐Ubiquitin complex to inhibit ubiquitin transfer, regardless of what the substrate is. Our results suggest a new mechanism of inhibition of MDM2 E3 activity for a broad spectrum of substrates.
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1878430
- Journal Information:
- Protein Science, Journal Name: Protein Science Journal Issue: 8 Vol. 31; ISSN 0961-8368
- Publisher:
- Wiley Blackwell (John Wiley & Sons)Copyright Statement
- Country of Publication:
- United Kingdom
- Language:
- English
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