1X9D: Crystal Structure Of Human Class I Alpha-1,2-mannosidase In Complex With Thio-disaccharide Substrate Analogue

Quality control in the endoplasmic reticulum (ER) determines the fate of newly synthesized glycoproteins toward either correct folding or disposal by ER-associated degradation. Initiation of the disposal process involves selective trimming of N-glycans attached to misfolded glycoproteins by ER alpha-mannosidase I and subsequent recognition by the ER degradation-enhancing alpha-mannosidase-like protein family of lectins, both members of glycosylhydrolase family 47. The unusual inverting hydrolytic mechanism catalyzed by members of this family is investigated here by a combination of kinetic and binding analyses of wild type and mutant forms of human ER alpha-mannosidase I as well as by structural analysis of a co-complex with an uncleaved thiodisaccharide substrate analog. These data reveal the roles of potential catalytic acid and base residues and the identification of a novel (3)S(1) sugar conformation for the bound substrate analog. The co-crystal structure described here, in combination with the (1)C(4) conformation of a previously identified co-complex with the glycone mimic, 1-deoxymannojirimycin, indicates that glycoside bond cleavage proceeds through a least motion conformational twist of a properly predisposed substrate in the -1 subsite. A novel (3)H(4) conformation is proposed as the exploded transition state.
PDB ID: 1X9DDownload
MMDB ID: 31959
PDB Deposition Date: 2004/8/20
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.41  Å
Source Organism:
Similar Structures:
Biological Unit for 1X9D: monomeric; determined by author
Molecular Components in 1X9D
Label Count Molecule
Protein (1 molecule)
Endoplasmic Reticulum Mannosyl-oligosaccharide 1,2-alpha- Mannosidase(Gene symbol: MAN1B1)
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB