1now: Difference between revisions
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|PDB= 1now |SIZE=350|CAPTION= <scene name='initialview01'>1now</scene>, resolution 2.20Å | |PDB= 1now |SIZE=350|CAPTION= <scene name='initialview01'>1now</scene>, resolution 2.20Å | ||
|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand= | |LIGAND= <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IFG:(2R,3R,4S,5R)-2-ACETAMIDO-3,4-DIHYDROXY-5-HYDROXYMETHYL-PIPERIDINE'>IFG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1now FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1now OCA], [http://www.ebi.ac.uk/pdbsum/1now PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1now 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). | ||
==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: (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 22:33:24 2008'' | ||