3GZN

Structure of NEDD8-activating enzyme in complex with NEDD8 and MLN4924

Summary for 3GZN

• Entry DOI: 10.2210/pdb3gzn/pdb
• Descriptor: NEDD8-activating enzyme E1 regulatory subunit, NEDD8-activating enzyme E1 catalytic subunit, NEDD8, ... (5 entities in total)
• Functional Keywords: nedd8, e1-activating enzyme, mln4924, protein binding-ligase complex, protein binding/ligase
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane: Q13564; Nucleus: Q15843
• Total number of polymer chains: 6
• Total formula weight: 244266.13

Authors

Sintchak, M.D. (deposition date: 2009-04-07, release date: 2010-02-02, Last modification date: 2024-11-20)

Primary citation

Brownell, J.E.,Sintchak, M.D.,Gavin, J.M.,Liao, H.,Bruzzese, F.J.,Bump, N.J.,Soucy, T.A.,Milhollen, M.A.,Yang, X.,Burkhardt, A.L.,Ma, J.,Loke, H.K.,Lingaraj, T.,Wu, D.,Hamman, K.B.,Spelman, J.J.,Cullis, C.A.,Langston, S.P.,Vyskocil, S.,Sells, T.B.,Mallender, W.D.,Visiers, I.,Li, P.,Claiborne, C.F.,Rolfe, M.,Bolen, J.B.,Dick, L.R.
Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ.
Mol.Cell, 37:102-111, 2010

PubMed Abstract: 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.

PubMed: 20129059
DOI: 10.1016/j.molcel.2009.12.024

Experimental method

X-RAY DIFFRACTION (3 Å)