PDBsum entry 4mj4

Hydrolase

PDB id: 4mj4

Contents

Protein chain

603 a.a.

Ligands

NAG-NAG-BMA-MAN-MAN

GOL ×3

NAG ×2

Metals

_CL

Waters ×116

PDB id:

4mj4

Name:

Hydrolase

Title:

Human iduronidase apo structure p21 form

Structure:

Alpha-l-iduronidase. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: idua. Expressed in: arabidopsis thaliana. Expression_system_taxid: 3702.

Resolution:

2.17Å R-factor: 0.203 R-free: 0.240

Authors:

H.Bie,J.Yin,X.He,A.R.Kermode,E.D.Goddard-Borger,S.G.Withers, M.N.G.James

Key ref:

H.Bie et al. (2013). Insights into mucopolysaccharidosis I from the structure and action of α-L-iduronidase. Nat Chem Biol, 9, 739-745. PubMed id: 24036510 DOI: 10.1038/nchembio.1357

Date:

03-Sep-13 Release date: 18-Sep-13

Supersedes:

4jxp

Protein chain

P35475  (IDUA_HUMAN) -  Alpha-L-iduronidase from Homo sapiens

Seq: 653 a.a.

Struc: 603 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.2.1.76 - L-iduronidase.
• Reaction: Hydrolysis of alpha-L-iduronosidic linkages in desulfated dermatan.

DOI no: 10.1038/nchembio.1357

Nat Chem Biol 9:739-745 (2013)

PubMed id: 24036510

Insights into mucopolysaccharidosis I from the structure and action of α-L-iduronidase.

H.Bie, J.Yin, X.He, A.R.Kermode, E.D.Goddard-Borger, S.G.Withers, M.N.James.

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.