1jak
From Proteopedia
(New page: 200px<br /> <applet load="1jak" size="450" color="white" frame="true" align="right" spinBox="true" caption="1jak, resolution 1.75Å" /> '''Streptomyces plicat...) |
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| - | [[Image:1jak.gif|left|200px]]<br /> | + | [[Image:1jak.gif|left|200px]]<br /><applet load="1jak" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1jak" size=" | + | |
caption="1jak, resolution 1.75Å" /> | caption="1jak, resolution 1.75Å" /> | ||
'''Streptomyces plicatus beta-N-acetylhexosaminidase in Complex with (2R,3R,4S,5R)-2-acetamido-3,4-dihydroxy-5-hydroxymethyl-piperidinium chloride (IFG)'''<br /> | '''Streptomyces plicatus beta-N-acetylhexosaminidase in Complex with (2R,3R,4S,5R)-2-acetamido-3,4-dihydroxy-5-hydroxymethyl-piperidinium chloride (IFG)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Azasugar inhibitors of the isofagomine class are potent competitive | + | Azasugar inhibitors of the isofagomine class are potent competitive inhibitors of configuration-retaining beta-glycosidases. This potency results from the formation of a strong electrostatic interaction between a protonated endocyclic nitrogen at the "anomeric" center of the inhibitor and the catalytic nucleophile of the enzyme. Although the majority of retaining beta-glycosidases use a mechanism involving a carboxylate residue as a nucleophile, Streptomyces plicatus beta-N-acetylhexos-aminidase (SpHEX) and related family 20 glycosidases lack such a catalytic residue and use instead the carbonyl oxygen of the 2-acetamido group of the substrate as a nucleophile to "attack" the anomeric center. Thus, a strong electrostatic interaction between the inhibitor and enzyme is not expected to occur; nonetheless, the 1-N-azasugar (2R,3R,4S,5R)-2-acetamido-3,4-dihydroxy-5-hydroxymethyl-piperidinium hydrochloride (GalNAc-isofagomine.HCl), which was synthesized and assayed for its ability to inhibit SpHEX, was found to be a potent competitive inhibitor of the enzyme (K(i) = 2.7 microm). A crystallographic complex of GalNAc-isofagomine bound to SpHEX was solved and refined to 1.75 A and revealed that the lack of a strong electrostatic interaction between the "anomeric" center of GalNAc-isofagomine and SpHEX is compensated for by a novel 2.8-A hydrogen bond formed between the equatorial proton of the endocyclic nitrogen of the azasugar ring and the carboxylate of the general acid-base residue Glu-314 of SpHEX. This interaction appears to contribute to the unexpected potency of GalNAc-isofagomine toward SpHEX. |
==About this Structure== | ==About this Structure== | ||
| - | 1JAK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptomyces_plicatus Streptomyces plicatus] with SO4, CL, IFG and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Beta-N-acetylhexosaminidase Beta-N-acetylhexosaminidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.52 3.2.1.52] Full crystallographic information is available from [http:// | + | 1JAK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptomyces_plicatus Streptomyces plicatus] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=IFG:'>IFG</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Beta-N-acetylhexosaminidase Beta-N-acetylhexosaminidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.52 3.2.1.52] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JAK OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Streptomyces plicatus]] | [[Category: Streptomyces plicatus]] | ||
| - | [[Category: James, M | + | [[Category: James, M N.]] |
[[Category: Knapp, S.]] | [[Category: Knapp, S.]] | ||
| - | [[Category: Mark, B | + | [[Category: Mark, B L.]] |
| - | [[Category: Vocadlo, D | + | [[Category: Vocadlo, D J.]] |
| - | [[Category: Withers, S | + | [[Category: Withers, S G.]] |
[[Category: Zhao, D.]] | [[Category: Zhao, D.]] | ||
[[Category: CL]] | [[Category: CL]] | ||
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[[Category: substrate-assisted catalysis]] | [[Category: substrate-assisted catalysis]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:20:26 2008'' |
Revision as of 11:20, 21 February 2008
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Streptomyces plicatus beta-N-acetylhexosaminidase in Complex with (2R,3R,4S,5R)-2-acetamido-3,4-dihydroxy-5-hydroxymethyl-piperidinium chloride (IFG)
Overview
Azasugar inhibitors of the isofagomine class are potent competitive inhibitors of configuration-retaining beta-glycosidases. This potency results from the formation of a strong electrostatic interaction between a protonated endocyclic nitrogen at the "anomeric" center of the inhibitor and the catalytic nucleophile of the enzyme. Although the majority of retaining beta-glycosidases use a mechanism involving a carboxylate residue as a nucleophile, Streptomyces plicatus beta-N-acetylhexos-aminidase (SpHEX) and related family 20 glycosidases lack such a catalytic residue and use instead the carbonyl oxygen of the 2-acetamido group of the substrate as a nucleophile to "attack" the anomeric center. Thus, a strong electrostatic interaction between the inhibitor and enzyme is not expected to occur; nonetheless, the 1-N-azasugar (2R,3R,4S,5R)-2-acetamido-3,4-dihydroxy-5-hydroxymethyl-piperidinium hydrochloride (GalNAc-isofagomine.HCl), which was synthesized and assayed for its ability to inhibit SpHEX, was found to be a potent competitive inhibitor of the enzyme (K(i) = 2.7 microm). A crystallographic complex of GalNAc-isofagomine bound to SpHEX was solved and refined to 1.75 A and revealed that the lack of a strong electrostatic interaction between the "anomeric" center of GalNAc-isofagomine and SpHEX is compensated for by a novel 2.8-A hydrogen bond formed between the equatorial proton of the endocyclic nitrogen of the azasugar ring and the carboxylate of the general acid-base residue Glu-314 of SpHEX. This interaction appears to contribute to the unexpected potency of GalNAc-isofagomine toward SpHEX.
About this Structure
1JAK is a Single protein structure of sequence from Streptomyces plicatus with , , and as ligands. Active as Beta-N-acetylhexosaminidase, with EC number 3.2.1.52 Full crystallographic information is available from OCA.
Reference
Biochemical and structural assessment of the 1-N-azasugar GalNAc-isofagomine as a potent family 20 beta-N-acetylhexosaminidase inhibitor., Mark BL, Vocadlo DJ, Zhao D, Knapp S, Withers SG, James MN, J Biol Chem. 2001 Nov 9;276(45):42131-7. Epub 2001 Aug 24. PMID:11522797
Page seeded by OCA on Thu Feb 21 13:20:26 2008
Categories: Beta-N-acetylhexosaminidase | Single protein | Streptomyces plicatus | James, M N. | Knapp, S. | Mark, B L. | Vocadlo, D J. | Withers, S G. | Zhao, D. | CL | GOL | IFG | SO4 | Alpha/beta barrel | Beta-n-acetylhexosaminidase | Family 20 | Glycoside hydrolase | Isofagomine inhibitor complex | Substrate-assisted catalysis
