1fo2

From Proteopedia

Revision as of 13:48, 15 February 2008

CRYSTAL STRUCTURE OF HUMAN CLASS I ALPHA1,2-MANNOSIDASE IN COMPLEX WITH 1-DEOXYMANNOJIRIMYCIN

Overview

Endoplasmic reticulum (ER) class I alpha1,2-mannosidase (also known as ER, alpha-mannosidase I) is a critical enzyme in the maturation of N-linked, oligosaccharides and ER-associated degradation. Trimming of a single, mannose residue acts as a signal to target misfolded glycoproteins for, degradation by the proteasome. Crystal structures of the catalytic domain, of human ER class I alpha1,2-mannosidase have been determined both in the, presence and absence of the potent inhibitors kifunensine and, 1-deoxymannojirimycin. Both inhibitors bind to the protein at the bottom, of the active-site cavity, with the essential calcium ion coordinating the, O-2' and O-3' hydroxyls and stabilizing the six-membered rings of both, inhibitors in a (1)C(4) conformation. This is the first direct evidence of, the role of the calcium ion. The lack of major conformational changes upon, inhibitor binding and structural comparisons with the yeast alpha1, 2-mannosidase enzyme-product complex suggest that this class of inverting, enzymes has a novel catalytic mechanism. The structures also provide, insight into the specificity of this class of enzymes and provide a, blueprint for the future design of novel inhibitors that prevent, degradation of misfolded proteins in genetic diseases.

About this Structure

1FO2 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Alpha-mannosidase, with EC number 3.2.1.24 Full crystallographic information is available from OCA.

Reference

Structural basis for catalysis and inhibition of N-glycan processing class I alpha 1,2-mannosidases., Vallee F, Karaveg K, Herscovics A, Moremen KW, Howell PL, J Biol Chem. 2000 Dec 29;275(52):41287-98. PMID:10995765

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