4KGJ

Crystal structure of human alpha-L-iduronidase complex with 5-fluoro-alpha-L-idopyranosyluronic acid fluoride

4KGJ の概要

• エントリーDOI: 10.2210/pdb4kgj/pdb
• 関連するPDBエントリー: 4JXO 4JXP 4KGL 4KH2
• 分子名称: Alpha-L-iduronidase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: glycoside hydrolase family 39, tim barrel, beta sandwich, fibronectin iii domain, glycosaminoglycans, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Lysosome: P35475
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 145276.59

構造登録者

Bie, H.,Yin, J.,He, X.,Kermode, A.R.,Goddard-Borger, E.D.,Withers, S.G.,James, M.N.G. (登録日: 2013-04-29, 公開日: 2013-09-18, 最終更新日: 2023-09-20)

主引用文献

Bie, H.,Yin, J.,He, X.,Kermode, A.R.,Goddard-Borger, E.D.,Withers, S.G.,James, M.N.
Insights into mucopolysaccharidosis I from the structure and action of alpha-L-iduronidase.
Nat.Chem.Biol., 9:739-745, 2013

PubMed Abstract: Mucopolysaccharidosis type I (MPS I), caused by mutations in the gene encoding α-L-iduronidase (IDUA), is one of approximately 70 genetic disorders collectively known as the lysosomal storage diseases. To gain insight into the basis for MPS I, we crystallized human IDUA produced in an Arabidopsis thaliana cgl mutant. IDUA consists of a TIM barrel domain containing the catalytic site, a β-sandwich domain and a fibronectin-like domain. Structures of IDUA bound to iduronate analogs illustrate the Michaelis complex and reveal a (2,5)B conformation in the glycosyl-enzyme intermediate, which suggest a retaining double displacement reaction involving the nucleophilic Glu299 and the general acid/base Glu182. Unexpectedly, the N-glycan attached to Asn372 interacts with iduronate analogs in the active site and is required for enzymatic activity. Finally, these IDUA structures and biochemical analysis of the disease-relevant P533R mutation have enabled us to correlate the effects of mutations in IDUA to clinical phenotypes.

PubMed: 24036510
DOI: 10.1038/nchembio.1357

実験手法

X-RAY DIFFRACTION (2.99 Å)