1np0
From Proteopedia
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|PDB= 1np0 |SIZE=350|CAPTION= <scene name='initialview01'>1np0</scene>, resolution 2.50Å | |PDB= 1np0 |SIZE=350|CAPTION= <scene name='initialview01'>1np0</scene>, resolution 2.50Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand= | + | |LIGAND= <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NGT:3AR,5R,6S,7R,7AR-5-HYDROXYMETHYL-2-METHYL-5,6,7,7A-TETRAHYDRO-3AH-PYRANO[3,2-D]THIAZOLE-6,7-DIOL'>NGT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> |
| - | |ACTIVITY= [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] | + | |ACTIVITY= <span class='plainlinks'>[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] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1nou|1NOU]], [[1now|1NOW]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1np0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1np0 OCA], [http://www.ebi.ac.uk/pdbsum/1np0 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1np0 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
In humans, two major beta-hexosaminidase isoenzymes exist: Hex A and Hex B. Hex A is a heterodimer of subunits alpha and beta (60% identity), whereas Hex B is a homodimer of beta-subunits. Interest in human beta-hexosaminidase stems from its association with Tay-Sachs and Sandhoff disease; these are prototypical lysosomal storage disorders resulting from the abnormal accumulation of G(M2)-ganglioside (G(M2)). Hex A degrades G(M2) by removing a terminal N-acetyl-D-galactosamine (beta-GalNAc) residue, and this activity requires the G(M2)-activator, a protein which solubilizes the ganglioside for presentation to Hex A. We present here the crystal structure of human Hex B, alone (2.4A) and in complex with the mechanistic inhibitors GalNAc-isofagomine (2.2A) or NAG-thiazoline (2.5A). From these, and the known X-ray structure of the G(M2)-activator, we have modeled Hex A in complex with the activator and ganglioside. Together, our crystallographic and modeling data demonstrate how alpha and beta-subunits dimerize to form either Hex A or Hex B, how these isoenzymes hydrolyze diverse substrates, and how many documented point mutations cause Sandhoff disease (beta-subunit mutations) and Tay-Sachs disease (alpha-subunit mutations). | In humans, two major beta-hexosaminidase isoenzymes exist: Hex A and Hex B. Hex A is a heterodimer of subunits alpha and beta (60% identity), whereas Hex B is a homodimer of beta-subunits. Interest in human beta-hexosaminidase stems from its association with Tay-Sachs and Sandhoff disease; these are prototypical lysosomal storage disorders resulting from the abnormal accumulation of G(M2)-ganglioside (G(M2)). Hex A degrades G(M2) by removing a terminal N-acetyl-D-galactosamine (beta-GalNAc) residue, and this activity requires the G(M2)-activator, a protein which solubilizes the ganglioside for presentation to Hex A. We present here the crystal structure of human Hex B, alone (2.4A) and in complex with the mechanistic inhibitors GalNAc-isofagomine (2.2A) or NAG-thiazoline (2.5A). From these, and the known X-ray structure of the G(M2)-activator, we have modeled Hex A in complex with the activator and ganglioside. Together, our crystallographic and modeling data demonstrate how alpha and beta-subunits dimerize to form either Hex A or Hex B, how these isoenzymes hydrolyze diverse substrates, and how many documented point mutations cause Sandhoff disease (beta-subunit mutations) and Tay-Sachs disease (alpha-subunit mutations). | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Sandhoff disease, infantile, juvenile, and adult forms OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606873 606873]], Spinal muscular atrophy, juvenile OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606873 606873]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Mark, B L.]] | [[Category: Mark, B L.]] | ||
[[Category: Zhao, D.]] | [[Category: Zhao, D.]] | ||
| - | [[Category: GOL]] | ||
| - | [[Category: NGT]] | ||
| - | [[Category: SO4]] | ||
[[Category: (beta/alpha)8-barrel]] | [[Category: (beta/alpha)8-barrel]] | ||
[[Category: family 20 glycosidase]] | [[Category: family 20 glycosidase]] | ||
[[Category: homodimer]] | [[Category: homodimer]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:33:26 2008'' |
Revision as of 19:33, 30 March 2008
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| , resolution 2.50Å | |||||||
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| Ligands: | , , , | ||||||
| Activity: | Beta-N-acetylhexosaminidase, with EC number 3.2.1.52 | ||||||
| Related: | 1NOU, 1NOW
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Human lysosomal beta-hexosaminidase isoform B in complex with intermediate analogue NAG-thiazoline
Overview
In humans, two major beta-hexosaminidase isoenzymes exist: Hex A and Hex B. Hex A is a heterodimer of subunits alpha and beta (60% identity), whereas Hex B is a homodimer of beta-subunits. Interest in human beta-hexosaminidase stems from its association with Tay-Sachs and Sandhoff disease; these are prototypical lysosomal storage disorders resulting from the abnormal accumulation of G(M2)-ganglioside (G(M2)). Hex A degrades G(M2) by removing a terminal N-acetyl-D-galactosamine (beta-GalNAc) residue, and this activity requires the G(M2)-activator, a protein which solubilizes the ganglioside for presentation to Hex A. We present here the crystal structure of human Hex B, alone (2.4A) and in complex with the mechanistic inhibitors GalNAc-isofagomine (2.2A) or NAG-thiazoline (2.5A). From these, and the known X-ray structure of the G(M2)-activator, we have modeled Hex A in complex with the activator and ganglioside. Together, our crystallographic and modeling data demonstrate how alpha and beta-subunits dimerize to form either Hex A or Hex B, how these isoenzymes hydrolyze diverse substrates, and how many documented point mutations cause Sandhoff disease (beta-subunit mutations) and Tay-Sachs disease (alpha-subunit mutations).
About this Structure
1NP0 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Crystal structure of human beta-hexosaminidase B: understanding the molecular basis of Sandhoff and Tay-Sachs disease., Mark BL, Mahuran DJ, Cherney MM, Zhao D, Knapp S, James MN, J Mol Biol. 2003 Apr 11;327(5):1093-109. PMID:12662933
Page seeded by OCA on Sun Mar 30 22:33:26 2008
