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1now
From Proteopedia
(New page: 200px<br /> <applet load="1now" size="450" color="white" frame="true" align="right" spinBox="true" caption="1now, resolution 2.20Å" /> '''Human lysosomal bet...) |
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caption="1now, resolution 2.20Å" /> | caption="1now, resolution 2.20Å" /> | ||
'''Human lysosomal beta-hexosaminidase isoform B in complex with (2R,3R,4S,5R)-2-Acetamido-3,4-Dihydroxy-5-Hydroxymethyl-Piperidinium Chloride (GalNAc-isofagomine)'''<br /> | '''Human lysosomal beta-hexosaminidase isoform B in complex with (2R,3R,4S,5R)-2-Acetamido-3,4-Dihydroxy-5-Hydroxymethyl-Piperidinium Chloride (GalNAc-isofagomine)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | In humans, two major beta-hexosaminidase isoenzymes exist: Hex A and Hex | + | 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). |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1NOW 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 SO4, 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:// | + | 1NOW 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=SO4:'>SO4</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=1NOW OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Cherney, M | + | [[Category: Cherney, M M.]] |
| - | [[Category: James, M | + | [[Category: James, M N.G.]] |
[[Category: Knapp, S.]] | [[Category: Knapp, S.]] | ||
| - | [[Category: Mahuran, D | + | [[Category: Mahuran, D J.]] |
| - | [[Category: Mark, B | + | [[Category: Mark, B L.]] |
[[Category: Zhao, D.]] | [[Category: Zhao, D.]] | ||
[[Category: GOL]] | [[Category: GOL]] | ||
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[[Category: homodimer]] | [[Category: homodimer]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:08:23 2008'' |
Revision as of 12:08, 21 February 2008
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Human lysosomal beta-hexosaminidase isoform B in complex with (2R,3R,4S,5R)-2-Acetamido-3,4-Dihydroxy-5-Hydroxymethyl-Piperidinium Chloride (GalNAc-isofagomine)
Contents |
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).
Disease
Known diseases associated with this structure: Sandhoff disease, infantile, juvenile, and adult forms OMIM:[606873], Spinal muscular atrophy, juvenile OMIM:[606873]
About this Structure
1NOW is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Beta-N-acetylhexosaminidase, with EC number 3.2.1.52 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
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