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PDBsum entry 2fue
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References listed in PDB file
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Key reference
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Title
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The X-Ray crystal structures of human alpha-Phosphomannomutase 1 reveal the structural basis of congenital disorder of glycosylation type 1a.
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Authors
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N.R.Silvaggi,
C.Zhang,
Z.Lu,
J.Dai,
D.Dunaway-Mariano,
K.N.Allen.
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Ref.
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J Biol Chem, 2006,
281,
14918-14926.
[DOI no: ]
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PubMed id
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Abstract
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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.
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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.
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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).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2006,
281,
14918-14926)
copyright 2006.
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