1X9D

Crystal Structure Of Human Class I alpha-1,2-Mannosidase In Complex With Thio-Disaccharide Substrate Analogue

Summary for 1X9D

• Entry DOI: 10.2210/pdb1x9d/pdb
• Related: 1FMI
• Related PRD ID: PRD_900033
• Descriptor: Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase, alpha-D-mannopyranose-(1-2)-methyl 2-thio-alpha-D-mannopyranoside, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: mannosidase, substrate analogue, glycosyl hydrolase, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane ; Single-pass type II membrane protein : Q9UKM7
• Total number of polymer chains: 1
• Total formula weight: 62028.18

Authors

Karaveg, K.,Tempel, W.,Liu, Z.J.,Siriwardena, A.,Moremen, K.W.,Wang, B.C. (deposition date: 2004-08-20, release date: 2005-02-22, Last modification date: 2024-11-20)

Primary citation

Karaveg, K.,Siriwardena, A.,Tempel, W.,Liu, Z.J.,Glushka, J.,Wang, B.C.,Moremen, K.W.
Mechanism of class 1 (glycosylhydrolase family 47) {alpha}-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control.
J.Biol.Chem., 280:16197-16207, 2005

PubMed Abstract: 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.

PubMed: 15713668
DOI: 10.1074/jbc.M500119200

Experimental method

X-RAY DIFFRACTION (1.41 Å)