2fuc
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Human alpha-Phosphomannomutase 1 with Mg2+ cofactor bound
OverviewOverview
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.
About this StructureAbout this Structure
2FUC is a Single protein structure of sequence from Homo sapiens with MG as ligand. Active as Phosphomannomutase, with EC number 5.4.2.8 Full crystallographic information is available from OCA.
ReferenceReference
The X-ray crystal structures of human alpha-phosphomannomutase 1 reveal the structural basis of congenital disorder of glycosylation type 1a., Silvaggi NR, Zhang C, Lu Z, Dai J, Dunaway-Mariano D, Allen KN, J Biol Chem. 2006 May 26;281(21):14918-26. Epub 2006 Mar 15. PMID:16540464
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