PDBsum entry: 3eju

Hydrolase

PDB id: 3eju

Contents

Protein chain

1016 a.a. *

Ligands

NAG

MRD

HN7

Metals

_ZN

Waters ×1115

* Residue conservation analysis

PDB id:

3eju

Name:

Hydrolase

Title:

Golgi alpha-mannosidase ii in complex with 5-substituted swa analog:(5s)-5-[2'-oxo-2'-(4-tert-butylphenyl)ethyl]-swainso

Structure:

Alpha-mannosidase 2. Chain: a. Fragment: catalytic domain. Unp residues 76-1108. Synonym: alpha-mannosidase ii, aman ii, man ii, mannosyl- oligosaccharide 1,3-1,6-alpha-mannosidase, golgi alpha-mann ii. Engineered: yes

Source:

Drosophila melanogaster. Fruit fly. Organism_taxid: 7227. Gene: alpha-man-ii, gmii. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227.

Resolution:

1.32Å R-factor: 0.155 R-free: 0.171

Authors:

D.A.Kuntz,K.Shea,D.R.Rose

Key ref:

D.A.Kuntz et al. (2010). Structural investigation of the binding of 5-substituted swainsonine analogues to Golgi alpha-mannosidase II. Chembiochem, 11, 673-680. PubMed id: 20209559

Date:

18-Sep-08 Release date: 13-Oct-09

Protein chain

Q24451  (MAN2_DROME) -  Alpha-mannosidase 2

Seq: 1108 a.a.

Struc: 1016 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.2.1.114 - Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase.
• Pathway: Mannosyl-glycoprotein N-acetylglucosaminyltransferases
• Reaction: Hydrolysis of the terminal 1,3- and 1,6-linked alpha-D-mannose residues in the mannosyl-oligosaccharide Man(5)(GlcNAc)(3).

 Gene Ontology (GO) functional annotation 

• Cellular component: membrane (6 terms)
• Biological process: metabolic process (3 terms)
• Biochemical function: catalytic activity (11 terms)

Chembiochem 11:673-680 (2010)

PubMed id: 20209559

Structural investigation of the binding of 5-substituted swainsonine analogues to Golgi alpha-mannosidase II.

D.A.Kuntz, S.Nakayama, K.Shea, H.Hori, Y.Uto, H.Nagasawa, D.R.Rose.

ABSTRACT

Golgi alpha-mannosidase II (GMII) is a key enzyme in the N-glycosylation pathway and is a potential target for cancer chemotherapy. The natural product swainsonine is a potent inhibitor of GMII. In this paper we characterize the binding of 5alpha-substituted swainsonine analogues to the soluble catalytic domain of Drosophila GMII by X-ray crystallography. These inhibitors enjoy an advantage over previously reported GMII inhibitors in that they did not significantly decrease the inhibitory potential of the swainsonine head-group. The phenyl groups of these analogues occupy a portion of the binding site not previously seen to be populated with either substrate analogues or other inhibitors and they form novel hydrophobic interactions. They displace a well-organized water cluster, but the presence of a C(10) carbonyl allows the reestablishment of important hydrogen bonds. Already approximately tenfold more active against the Golgi enzyme than the lysosomal enzyme, these inhibitors offer the potential of being extended into the N-acetylglucosamine binding site of GMII for the creation of even more potent and selective GMII inhibitors.