PDBsum entry: 1hxk

Hydrolase

PDB id: 1hxk

Contents

Protein chain

1014 a.a. *

Ligands

NAG

DMJ

MRD

Metals

_ZN

Waters ×983

* Residue conservation analysis

PDB id:

1hxk

Name:

Hydrolase

Title:

Golgi alpha-mannosidase ii in complex with deoxymannojirimic

Structure:

Alpha-mannosidase ii. Chain: a. Synonym: golgi alpha-mannosidase ii. Engineered: yes

Source:

Drosophila melanogaster. Fruit fly. Organism_taxid: 7227. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227. Expression_system_cell: s2

Resolution:

1.50Å R-factor: 0.197 R-free: 0.216

Authors:

J.M.H.Van Den Elsen,D.A.Kuntz,D.R.Rose

Key ref:

J.M.van den Elsen et al. (2001). Structure of Golgi alpha-mannosidase II: a target for inhibition of growth and metastasis of cancer cells. EMBO J, 20, 3008-3017. PubMed id: 11406577 DOI: 10.1093/emboj/20.12.3008

Date:

16-Jan-01 Release date: 16-Jan-02

Protein chain

Q24451  (MAN2_DROME) -  Alpha-mannosidase 2

Seq: 1108 a.a.

Struc: 1014 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)

DOI no: 10.1093/emboj/20.12.3008

EMBO J 20:3008-3017 (2001)

PubMed id: 11406577

Structure of Golgi alpha-mannosidase II: a target for inhibition of growth and metastasis of cancer cells.

J.M.van den Elsen, D.A.Kuntz, D.R.Rose.

ABSTRACT

Golgi alpha-mannosidase II, a key enzyme in N-glycan processing, is a target in the development of anti- cancer therapies. The crystal structure of Drosophila Golgi alpha-mannosidase II in the absence and presence of the anti-cancer agent swainsonine and the inhibitor deoxymannojirimycin reveals a novel protein fold with an active site zinc intricately involved both in the substrate specificity of the enzyme and directly in the catalytic mechanism. Identification of a putative GlcNAc binding pocket in the vicinity of the active site cavity provides a model for the binding of the GlcNAcMan(5)GlcNAc(2) substrate and the consecutive hydrolysis of the alpha1,6- and alpha1,3-linked mannose residues. The enzyme-inhibitor interactions observed provide insight into the catalytic mechanism, opening the door to the design of novel inhibitors of alpha-mannosidase II.

Selected figure(s)

Figure 1.
Figure 1 (A) Schematic representation of the high mannose GlcNAcMan[5]GlcNAc[2] substrate of dGMII. N-acetyl-glucosamine residues are shown as black hexagons, 1,6-linked mannose residues (M4 and M6) are colored in green, 1,3-linked mannose residues (M5 and M7) are colored in magenta and 1,4-linked mannose M3 is shown in red. (B) Ribbon representation of the dGMII structure, top view onto the planar surface; (C) side view. The planar and convex faces of the molecule are indicated. The loop formed by residues 527 -540 is shown in yellow. All molecular images were prepared using MOLSCRIPT (Kraulis, 1991) and rendered using Raster3D (Merritt and Bacon, 1997).

Figure 3.
Figure 3 Stereo views of the active site of dGMII with bound Tris (A), DMNJ (B) and swainsonine (C) molecules. The active site zinc ion is shown in turquoise, the bound inhibitor molecules are rendered in gold and water molecules are represented as transparent red spheres. Interatomic distances <3.2 Å are shown as blue dashed lines.

The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2001, 20, 3008-3017) copyright 2001.

Figures were selected by the author.