4KH2: Crystal Structure Of Human Alpha-l-iduronidase Complex With 2-deoxy-2- Fluoro-alpha-l-idopyranosyluronic Acid Fluoride

Citation:
Abstract
Mucopolysaccharidosis type I (MPS I), caused by mutations in the gene encoding alpha-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 beta-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.
PDB ID: 4KH2Download
MMDB ID: 113593
PDB Deposition Date: 2013/4/29
Updated in MMDB: 2013/11
Experimental Method:
x-ray diffraction
Resolution: 2.36  Å
Source Organism:
Similar Structures:
Biological Unit for 4KH2: monomeric; determined by software (PISA)
Molecular Components in 4KH2
Label Count Molecule
Protein (1 molecule)
1
Alpha-l-iduronidase(Gene symbol: IDUA)
Molecule annotation
Chemicals (15 molecules)
1
6
2
2
3
3
4
2
5
1
6
1
* Click molecule labels to explore molecular sequence information.

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