4KH2

Crystal structure of human alpha-L-iduronidase complex with 2-deoxy-2-fluoro-alpha-L-idopyranosyluronic acid fluoride

Summary for 4KH2

• Entry DOI: 10.2210/pdb4kh2/pdb
• Related: 4JXO 4JXP 4KGJ 4KGL
• Descriptor: Alpha-L-iduronidase, S,R MESO-TARTARIC ACID, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• Functional Keywords: glycoside hydrolase family 39, tim barrel, beta sandwich, fibronectin iii domain, glycosaminoglycans, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P35475
• Total number of polymer chains: 2
• Total formula weight: 145151.97

Authors

Bie, H.,Yin, J.,He, X.,Kermode, A.R.,Goddard-Borger, E.D.,Withers, S.G.,James, M.N.G. (deposition date: 2013-04-29, release date: 2013-09-18, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.36 Å)