1wuu
From Proteopedia
(New page: 200px<br /> <applet load="1wuu" size="450" color="white" frame="true" align="right" spinBox="true" caption="1wuu, resolution 2.5Å" /> '''crystal structure of...) |
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| - | [[Image:1wuu.gif|left|200px]]<br /> | + | [[Image:1wuu.gif|left|200px]]<br /><applet load="1wuu" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1wuu, resolution 2.5Å" /> | caption="1wuu, resolution 2.5Å" /> | ||
'''crystal structure of human galactokinase complexed with MgAMPPNP and galactose'''<br /> | '''crystal structure of human galactokinase complexed with MgAMPPNP and galactose'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Galactokinase functions in the Leloir pathway for galactose metabolism by | + | Galactokinase functions in the Leloir pathway for galactose metabolism by catalyzing the MgATP-dependent phosphorylation of the C-1 hydroxyl group of alpha-D-galactose. The enzyme is known to belong to the GHMP superfamily of small molecule kinases and has attracted significant research attention for well over 40 years. Approximately 20 mutations have now been identified in human galactokinase, which result in the diseased state referred to as Type II galactosemia. Here we report the three-dimensional architecture of human galactokinase with bound alpha-D-galactose and Mg-AMPPNP. The overall fold of the molecule can be described in terms of two domains with the active site wedged between them. The N-terminal domain is dominated by a six-stranded mixed beta-sheet whereas the C-terminal motif contains six alpha-helices and two layers of anti-parallel beta-sheet. Those residues specifically involved in sugar binding include Arg37, Glu43, His44, Asp46, Gly183, Asp186, and Tyr236. The C-1 hydroxyl group of alpha-D-galactose sits within 3.3 A of the gamma-phosphorus of the nucleotide and 3.4 A of the guanidinium group of Arg37. The carboxylate side chain of Asp186 lies within approximately 3.2 A of the C-2 hydroxyl group of alpha-D-galactose and the guanidinium group of Arg37. Both Arg37 and Asp186 are strictly conserved among both prokaryotic and eukaryotic galactokinases. In addition to providing molecular insight into the active site geometry of the enzyme, the model also provides a structural framework upon which to more fully understand the consequences of the those mutations known to give rise to Type II galactosemia. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1WUU 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 GLA, MG and ANP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Galactokinase Galactokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.6 2.7.1.6] Full crystallographic information is available from [http:// | + | 1WUU 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=GLA:'>GLA</scene>, <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=ANP:'>ANP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Galactokinase Galactokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.6 2.7.1.6] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1WUU OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Holden, H | + | [[Category: Holden, H M.]] |
| - | [[Category: Reece, R | + | [[Category: Reece, R J.]] |
| - | [[Category: Thoden, J | + | [[Category: Thoden, J B.]] |
| - | [[Category: Timson, D | + | [[Category: Timson, D J.]] |
[[Category: ANP]] | [[Category: ANP]] | ||
[[Category: GLA]] | [[Category: GLA]] | ||
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[[Category: kinase]] | [[Category: kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:48:19 2008'' |
Revision as of 13:48, 21 February 2008
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crystal structure of human galactokinase complexed with MgAMPPNP and galactose
Contents |
Overview
Galactokinase functions in the Leloir pathway for galactose metabolism by catalyzing the MgATP-dependent phosphorylation of the C-1 hydroxyl group of alpha-D-galactose. The enzyme is known to belong to the GHMP superfamily of small molecule kinases and has attracted significant research attention for well over 40 years. Approximately 20 mutations have now been identified in human galactokinase, which result in the diseased state referred to as Type II galactosemia. Here we report the three-dimensional architecture of human galactokinase with bound alpha-D-galactose and Mg-AMPPNP. The overall fold of the molecule can be described in terms of two domains with the active site wedged between them. The N-terminal domain is dominated by a six-stranded mixed beta-sheet whereas the C-terminal motif contains six alpha-helices and two layers of anti-parallel beta-sheet. Those residues specifically involved in sugar binding include Arg37, Glu43, His44, Asp46, Gly183, Asp186, and Tyr236. The C-1 hydroxyl group of alpha-D-galactose sits within 3.3 A of the gamma-phosphorus of the nucleotide and 3.4 A of the guanidinium group of Arg37. The carboxylate side chain of Asp186 lies within approximately 3.2 A of the C-2 hydroxyl group of alpha-D-galactose and the guanidinium group of Arg37. Both Arg37 and Asp186 are strictly conserved among both prokaryotic and eukaryotic galactokinases. In addition to providing molecular insight into the active site geometry of the enzyme, the model also provides a structural framework upon which to more fully understand the consequences of the those mutations known to give rise to Type II galactosemia.
Disease
Known diseases associated with this structure: Galactokinase deficiency with cataracts OMIM:[604313]
About this Structure
1WUU is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Galactokinase, with EC number 2.7.1.6 Full crystallographic information is available from OCA.
Reference
Molecular structure of human galactokinase: implications for type II galactosemia., Thoden JB, Timson DJ, Reece RJ, Holden HM, J Biol Chem. 2005 Mar 11;280(10):9662-70. Epub 2004 Dec 7. PMID:15590630
Page seeded by OCA on Thu Feb 21 15:48:19 2008
Categories: Galactokinase | Homo sapiens | Single protein | Holden, H M. | Reece, R J. | Thoden, J B. | Timson, D J. | ANP | GLA | MG | Galactosemia | Ghmp superfamily | Kinase
