2fuc: Difference between revisions

Revision as of 18:25, 21 February 2008

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 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

Page seeded by OCA on Thu Feb 21 17:25:15 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[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="450" color="white" frame="true" align="right" spinBox="true"
 caption="2fuc, resolution 2.10&Aring;" />
 '''Human alpha-Phosphomannomutase 1 with Mg2+ cofactor bound'''<br />
 ==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.
+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==
-FUC 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2FUC OCA].
+FUC 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==
@@ Line 15: / Line 14: @@
 [[Category: Phosphomannomutase]]
 [[Category: Single protein]]
-[[Category: Allen, K.N.]]
+[[Category: Allen, K N.]]
 [[Category: Dunaway-Mariano, D.]]
 [[Category: Lu, Z.]]
-[[Category: Silvaggi, N.R.]]
+[[Category: Silvaggi, N R.]]
 [[Category: Zhang, C.]]
 [[Category: MG]]
@@ Line 26: / Line 25: @@
 [[Category: protein glycosylation]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:10:22 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:25:15 2008''