PDBsum entry 2fue

Isomerase

PDB id: 2fue

Contents

Protein chain

246 a.a. *

Ligands

M1P

Metals

_MG ×2

Waters ×238

* Residue conservation analysis

PDB id:

2fue

Name:

Isomerase

Title:

Human alpha-phosphomannomutase 1 with d-mannose 1-phosphate and mg2+ cofactor bound

Structure:

Phosphomannomutase 1. Chain: a. Synonym: pmm 1, pmmh-22. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PDB file)

Resolution:

1.75Å R-factor: 0.204 R-free: 0.240

Authors:

N.R.Silvaggi,C.Zhang,Z.Lu,D.Dunaway-Mariano,K.N.Allen

Key ref:

N.R.Silvaggi et al. (2006). The X-ray crystal structures of human alpha-phosphomannomutase 1 reveal the structural basis of congenital disorder of glycosylation type 1a. J Biol Chem, 281, 14918-14926. PubMed id: 16540464 DOI: 10.1074/jbc.M601505200

Date:

26-Jan-06 Release date: 21-Mar-06

Protein chain

Q92871  (PMM1_HUMAN) -  Phosphomannomutase 1 from Homo sapiens

Seq: 262 a.a.

Struc: 246 a.a.

Enzyme reactions

• Enzyme class: E.C.5.4.2.8 - phosphomannomutase.
• Pathway: GDP-L-Fucose and GDP-mannose Biosynthesis
• Reaction: alpha-D-mannose 1-phosphate = D-mannose 6-phosphate

alpha-D-mannose 1-phosphate (Bound ligand (Het Group name = M1P) corresponds exactly) = D-mannose 6-phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1074/jbc.M601505200

J Biol Chem 281:14918-14926 (2006)

PubMed id: 16540464

The X-ray crystal structures of human alpha-phosphomannomutase 1 reveal the structural basis of congenital disorder of glycosylation type 1a.

N.R.Silvaggi, C.Zhang, Z.Lu, J.Dai, D.Dunaway-Mariano, K.N.Allen.

ABSTRACT

Congenital disorder of glycosylation type 1a (CDG-1a) is a congenital disease characterized by severe defects in nervous system development. It is caused by mutations in alpha-phosphomannomutase (of which there are two isozymes, alpha-PMM1 and alpha-PPM2). Here we report the x-ray crystal structures of human alpha-PMM1 in the open conformation, with and without the bound substrate, alpha-D-mannose 1-phosphate. Alpha-PMM1, like most haloalkanoic acid dehalogenase superfamily (HADSF) members, consists of two domains, the cap and core, which open to bind substrate and then close to provide a solvent-exclusive environment for catalysis. The substrate phosphate group is observed at a positively charged site of the cap domain, rather than at the core domain phosphoryl-transfer site defined by the Asp(19) nucleophile and Mg(2+) cofactor. This suggests that substrate binds first to the cap and then is swept into the active site upon cap closure. The orientation of the acid/base residue Asp(21) suggests that alpha-phosphomannomutase (alpha-PMM) uses a different method of protecting the aspartylphosphate from hydrolysis than the HADSF member beta-phosphoglucomutase. It is hypothesized that the electrostatic repulsion of positive charges at the interface of the cap and core domains stabilizes alpha-PMM1 in the open conformation and that the negatively charged substrate binds to the cap, thereby facilitating its closure over the core domain. The two isozymes, alpha-PMM1 and alpha-PMM2, are shown to have a conserved active-site structure and to display similar kinetic properties. Analysis of the known mutation sites in the context of the structures reveals the genotype-phenotype relationship underlying CDG-1a.

Selected figure(s)

Figure 1.
FIGURE 1. Scheme for the reaction catalyzed by human -phosphomannomutase. The C-1 and C-6 positions on the hexose ring are labeled in the first step.

Figure 2.
FIGURE 2. A, structure of human -phosphomannomutase complexed with -D-mannose 1-phosphate. The cap domain is magenta and the core domain cyan. Man-1-P is shown as ball-and-stick (orange) and the two Mg^2+ ions as metallic spheres. The image was rendered using MOL-SCRIPT (38) and POVRAY. B, schematic representation of the arrangement of secondary structure elements in -PMM1 core (cyan) and cap (magenta).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 14918-14926) copyright 2006.

Figures were selected by an automated process.