2FUC

Human alpha-Phosphomannomutase 1 with Mg2+ cofactor bound

Summary for 2FUC

• Entry DOI: 10.2210/pdb2fuc/pdb
• Related: 2FUE
• Descriptor: Phosphomannomutase 1, MAGNESIUM ION (3 entities in total)
• Functional Keywords: phosphomannomutase, protein glycosylation, carbohydrate-deficient glycoprotein syndrome, haloalkanoic acid dehalogenase superfamily, isomerase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q92871
• Total number of polymer chains: 1
• Total formula weight: 30023.00

Authors

Silvaggi, N.R.,Zhang, C.,Lu, Z.,Dunaway-Mariano, D.,Allen, K.N. (deposition date: 2006-01-26, release date: 2006-03-21, Last modification date: 2017-10-18)

Primary citation

Silvaggi, N.R.,Zhang, C.,Lu, Z.,Dai, J.,Dunaway-Mariano, D.,Allen, K.N.
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, 2006

PubMed 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.

PubMed: 16540464
DOI: 10.1074/jbc.M601505200

Experimental method

X-RAY DIFFRACTION (2.1 Å)