Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ
| Autor: | Anne L. Burkhardt, Michael Milhollen, Xiaofeng Yang, Huay-Keng Loke, Lawrence R. Dick, Teresa A. Soucy, Irache Visiers, Frank J. Bruzzese, Michael D. Sintchak, James J. Spelman, Steven P. Langston, Ping Li, Kristin B. Hamman, James M. Gavin, Joseph B. Bolen, Nancy Bump, Sells Todd B, Jingya Ma, Christopher F. Claiborne, Stepan Vyskocil, Courtney Cullis, Hua Liao, Mark Rolfe, Dongyun Wu, James E. Brownell, Trupti Lingaraj, William D. Mallender |
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| Rok vydání: | 2009 |
| Předmět: |
NEDD8 Protein
Adenylate kinase Cyclopentanes Crystallography X-Ray NEDD8 Binding Competitive Protein neddylation Ubiquitin Cell Line Tumor NEDD8 Activating Enzyme Humans Enzyme Inhibitors Molecular Biology Ubiquitins chemistry.chemical_classification Binding Sites biology Active site Cell Biology Adenosine Monophosphate Protein Structure Tertiary Enzyme Activation Pevonedistat Enzyme Pyrimidines chemistry Biochemistry biology.protein |
| Zdroj: | Molecular cell. 37(1) |
| ISSN: | 1097-4164 |
| Popis: | The NEDD8-activating enzyme (NAE) initiates a protein homeostatic pathway essential for cancer cell growth and survival. MLN4924 is a selective inhibitor of NAE currently in clinical trials for the treatment of cancer. Here, we show that MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924. Importantly, we have determined that compounds resembling MLN4924 demonstrate the ability to form analogous adducts with other ubiquitin-like proteins (UBLs) catalyzed by their cognate-activating enzymes. These findings reveal insights into the mechanism of E1s and suggest a general strategy for selective inhibition of UBL conjugation pathways. |
| Databáze: | OpenAIRE |
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