3GZN

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

3GZN の概要

• エントリーDOI: 10.2210/pdb3gzn/pdb
• 分子名称: NEDD8-activating enzyme E1 regulatory subunit, NEDD8-activating enzyme E1 catalytic subunit, NEDD8, ... (5 entities in total)
• 機能のキーワード: nedd8, e1-activating enzyme, mln4924, protein binding-ligase complex, protein binding/ligase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cell membrane: Q13564; Nucleus: Q15843
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 244266.13

構造登録者

Sintchak, M.D. (登録日: 2009-04-07, 公開日: 2010-02-02, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3 Å)