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| - | [[Image:2fuc.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2fuc| PDB=2fuc | SCENE= }} | | {{STRUCTURE_2fuc| PDB=2fuc | SCENE= }} |
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| - | '''Human alpha-Phosphomannomutase 1 with Mg2+ cofactor bound'''
| + | ===Human alpha-Phosphomannomutase 1 with Mg2+ cofactor bound=== |
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| - | ==Overview==
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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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_16540464}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 16540464 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_16540464}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Phosphomannomutase]] | | [[Category: Phosphomannomutase]] |
| | [[Category: Protein glycosylation]] | | [[Category: Protein glycosylation]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 04:19:06 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 12:44:41 2008'' |
Revision as of 09:44, 27 July 2008
Template:STRUCTURE 2fuc
Human alpha-Phosphomannomutase 1 with Mg2+ cofactor bound
Template:ABSTRACT PUBMED 16540464
About this Structure
2FUC is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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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