3MS5

Crystal Structure of Human gamma-butyrobetaine,2-oxoglutarate dioxygenase 1 (BBOX1)

3MS5 の概要

• エントリーDOI: 10.2210/pdb3ms5/pdb
• 分子名称: Gamma-butyrobetaine dioxygenase, NICKEL (II) ION, ZINC ION, ... (7 entities in total)
• 機能のキーワード: gamma-butyrobetaine hydroxylase, gamma-butyrobetaine, 2-oxoglutarate dioxygenase 1, structural genomics, structural genomics consortium, sgc, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45838.94

構造登録者

Krojer, T.,Kochan, G.,McDonough, M.A.,von Delft, F.,Leung, I.K.H.,Henry, L.,Claridge, T.D.W.,Pilka, E.,Ugochukwu, E.,Muniz, J.,Filippakopoulos, P.,Bountra, C.,Arrowsmith, C.H.,Weigelt, J.,Edwards, A.,Kavanagh, K.L.,Schofield, C.J.,Oppermann, U.,Structural Genomics Consortium (SGC) (登録日: 2010-04-29, 公開日: 2010-05-12, 最終更新日: 2024-02-21)

主引用文献

Leung, I.K.,Krojer, T.J.,Kochan, G.T.,Henry, L.,von Delft, F.,Claridge, T.D.,Oppermann, U.,McDonough, M.A.,Schofield, C.J.
Structural and mechanistic studies on gamma-butyrobetaine hydroxylase.
Chem. Biol., 17:1316-1324, 2010

PubMed Abstract: The final step in carnitine biosynthesis is catalyzed by γ-butyrobetaine (γBB) hydroxylase (BBOX), an iron/2-oxoglutarate (2OG) dependent oxygenase. BBOX is inhibited by trimethylhydrazine-propionate (THP), a clinically used compound. We report structural and mechanistic studies on BBOX and its reaction with THP. Crystallographic and sequence analyses reveal that BBOX and trimethyllysine hydroxylase form a subfamily of 2OG oxygenases that dimerize using an N-terminal domain. The crystal structure reveals the active site is enclosed and how THP competes with γBB. THP is a substrate giving formaldehyde (supporting structural links with histone demethylases), dimethylamine, malonic acid semi-aldehyde, and an unexpected product with an additional carbon-carbon bond resulting from N-demethylation coupled to oxidative rearrangement, likely via an unusual radical mechanism. The results provide a basis for development of improved BBOX inhibitors and may inspire the discovery of additional rearrangement reactions.

PubMed: 21168767
DOI: 10.1016/j.chembiol.2010.09.016

実験手法

X-RAY DIFFRACTION (1.82 Å)