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2fuc
From Proteopedia
(New page: 200px<br /> <applet load="2fuc" size="450" color="white" frame="true" align="right" spinBox="true" caption="2fuc, resolution 2.10Å" /> '''Human alpha-Phospho...) |
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| - | [[Image:2fuc.gif|left|200px]]<br /> | + | [[Image:2fuc.gif|left|200px]]<br /><applet load="2fuc" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2fuc" size=" | + | |
caption="2fuc, resolution 2.10Å" /> | caption="2fuc, resolution 2.10Å" /> | ||
'''Human alpha-Phosphomannomutase 1 with Mg2+ cofactor bound'''<br /> | '''Human alpha-Phosphomannomutase 1 with Mg2+ cofactor bound'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Congenital disorder of glycosylation type 1a (CDG-1a) is a congenital | + | 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 Structure== | ==About this Structure== | ||
| - | 2FUC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphomannomutase Phosphomannomutase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.4.2.8 5.4.2.8] Full crystallographic information is available from [http:// | + | 2FUC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphomannomutase Phosphomannomutase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.4.2.8 5.4.2.8] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FUC OCA]. |
==Reference== | ==Reference== | ||
| Line 15: | Line 14: | ||
[[Category: Phosphomannomutase]] | [[Category: Phosphomannomutase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Allen, K | + | [[Category: Allen, K N.]] |
[[Category: Dunaway-Mariano, D.]] | [[Category: Dunaway-Mariano, D.]] | ||
[[Category: Lu, Z.]] | [[Category: Lu, Z.]] | ||
| - | [[Category: Silvaggi, N | + | [[Category: Silvaggi, N R.]] |
[[Category: Zhang, C.]] | [[Category: Zhang, C.]] | ||
[[Category: MG]] | [[Category: MG]] | ||
| Line 26: | Line 25: | ||
[[Category: protein glycosylation]] | [[Category: protein glycosylation]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:25:15 2008'' |
Revision as of 15:25, 21 February 2008
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Human alpha-Phosphomannomutase 1 with Mg2+ cofactor bound
Overview
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 Structure
2FUC is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Phosphomannomutase, with EC number 5.4.2.8 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
Page seeded by OCA on Thu Feb 21 17:25:15 2008
