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| - | [[Image:1now.gif|left|200px]] | |
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| - | {{Structure
| + | ==Human lysosomal beta-hexosaminidase isoform B in complex with (2R,3R,4S,5R)-2-Acetamido-3,4-Dihydroxy-5-Hydroxymethyl-Piperidinium Chloride (GalNAc-isofagomine)== |
| - | |PDB= 1now |SIZE=350|CAPTION= <scene name='initialview01'>1now</scene>, resolution 2.20Å
| + | <StructureSection load='1now' size='340' side='right'caption='[[1now]], [[Resolution|resolution]] 2.20Å' scene=''> |
| - | |SITE=
| + | == Structural highlights == |
| - | |LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=IFG:(2R,3R,4S,5R)-2-ACETAMIDO-3,4-DIHYDROXY-5-HYDROXYMETHYL-PIPERIDINE'>IFG</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene> | + | <table><tr><td colspan='2'>[[1now]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NOW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1NOW FirstGlance]. <br> |
| - | |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]
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> |
| - | |GENE= | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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></td></tr> |
| - | }}
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1now FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1now OCA], [https://pdbe.org/1now PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1now RCSB], [https://www.ebi.ac.uk/pdbsum/1now PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1now ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/HEXB_HUMAN HEXB_HUMAN] Defects in HEXB are the cause of GM2-gangliosidosis type 2 (GM2G2) [MIM:[https://omim.org/entry/268800 268800]; also known as Sandhoff disease. GM2-gangliosidosis is an autosomal recessive lysosomal storage disease marked by the accumulation of GM2 gangliosides in the neuronal cells. GM2G2 is clinically indistinguishable from GM2-gangliosidosis type 1, presenting startle reactions, early blindness, progressive motor and mental deterioration, macrocephaly and cherry-red spots on the macula.<ref>PMID:1720305</ref> <ref>PMID:1531140</ref> <ref>PMID:8357844</ref> <ref>PMID:7626071</ref> <ref>PMID:7557963</ref> <ref>PMID:7633435</ref> <ref>PMID:8950198</ref> <ref>PMID:9401004</ref> <ref>PMID:9856491</ref> <ref>PMID:9694901</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/HEXB_HUMAN HEXB_HUMAN] Responsible for the degradation of GM2 gangliosides, and a variety of other molecules containing terminal N-acetyl hexosamines, in the brain and other tissues. |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/no/1now_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1now ConSurf]. |
| | + | <div style="clear:both"></div> |
| | | | |
| - | '''Human lysosomal beta-hexosaminidase isoform B in complex with (2R,3R,4S,5R)-2-Acetamido-3,4-Dihydroxy-5-Hydroxymethyl-Piperidinium Chloride (GalNAc-isofagomine)'''
| + | ==See Also== |
| - | | + | *[[Beta-Hexosaminidase|Beta-Hexosaminidase]] |
| - | | + | *[[Beta-Hexosaminidase 3D structures|Beta-Hexosaminidase 3D structures]] |
| - | ==Overview== | + | *[[Beta-N-acetylhexosaminidase 3D structures|Beta-N-acetylhexosaminidase 3D structures]] |
| - | 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).
| + | == References == |
| - | | + | <references/> |
| - | ==Disease==
| + | __TOC__ |
| - | 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]]
| + | </StructureSection> |
| - | | + | |
| - | ==About this Structure== | + | |
| - | 1NOW is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NOW 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:[http://www.ncbi.nlm.nih.gov/pubmed/12662933 12662933]
| + | |
| - | [[Category: Beta-N-acetylhexosaminidase]]
| + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Cherney, M M.]] | + | [[Category: Cherney MM]] |
| - | [[Category: James, M N.G.]] | + | [[Category: James MNG]] |
| - | [[Category: Knapp, S.]] | + | [[Category: Knapp S]] |
| - | [[Category: Mahuran, D J.]] | + | [[Category: Mahuran DJ]] |
| - | [[Category: Mark, B L.]] | + | [[Category: Mark BL]] |
| - | [[Category: Zhao, D.]] | + | [[Category: Zhao D]] |
| - | [[Category: GOL]]
| + | |
| - | [[Category: IFG]]
| + | |
| - | [[Category: SO4]]
| + | |
| - | [[Category: (beta/alpha)8-barrel]]
| + | |
| - | [[Category: family 20 glycosidase]]
| + | |
| - | [[Category: homodimer]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:59:41 2008''
| + | |
| Structural highlights
Disease
HEXB_HUMAN Defects in HEXB are the cause of GM2-gangliosidosis type 2 (GM2G2) [MIM:268800; also known as Sandhoff disease. GM2-gangliosidosis is an autosomal recessive lysosomal storage disease marked by the accumulation of GM2 gangliosides in the neuronal cells. GM2G2 is clinically indistinguishable from GM2-gangliosidosis type 1, presenting startle reactions, early blindness, progressive motor and mental deterioration, macrocephaly and cherry-red spots on the macula.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Function
HEXB_HUMAN Responsible for the degradation of GM2 gangliosides, and a variety of other molecules containing terminal N-acetyl hexosamines, in the brain and other tissues.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
See Also
References
- ↑ Banerjee P, Siciliano L, Oliveri D, McCabe NR, Boyers MJ, Horwitz AL, Li SC, Dawson G. Molecular basis of an adult form of beta-hexosaminidase B deficiency with motor neuron disease. Biochem Biophys Res Commun. 1991 Nov 27;181(1):108-15. PMID:1720305
- ↑ Wakamatsu N, Kobayashi H, Miyatake T, Tsuji S. A novel exon mutation in the human beta-hexosaminidase beta subunit gene affects 3' splice site selection. J Biol Chem. 1992 Feb 5;267(4):2406-13. PMID:1531140
- ↑ Bolhuis PA, Ponne NJ, Bikker H, Baas F, Vianney de Jong JM. Molecular basis of an adult form of Sandhoff disease: substitution of glutamine for arginine at position 505 of the beta-chain of beta-hexosaminidase results in a labile enzyme. Biochim Biophys Acta. 1993 Sep 8;1182(2):142-6. PMID:8357844
- ↑ Kuroki Y, Itoh K, Nadaoka Y, Tanaka T, Sakuraba H. A novel missense mutation (C522Y) is present in the beta-hexosaminidase beta-subunit gene of a Japanese patient with infantile Sandhoff disease. Biochem Biophys Res Commun. 1995 Jul 17;212(2):564-71. PMID:7626071 doi:http://dx.doi.org/10.1006/bbrc.1995.2007
- ↑ Gomez-Lira M, Sangalli A, Mottes M, Perusi C, Pignatti PF, Rizzuto N, Salviati A. A common beta hexosaminidase gene mutation in adult Sandhoff disease patients. Hum Genet. 1995 Oct;96(4):417-22. PMID:7557963
- ↑ Zhang ZX, Wakamatsu N, Akerman BR, Mules EH, Thomas GH, Gravel RA. A second, large deletion in the HEXB gene in a patient with infantile Sandhoff disease. Hum Mol Genet. 1995 Apr;4(4):777-80. PMID:7633435
- ↑ Redonnet-Vernhet I, Mahuran DJ, Salvayre R, Dubas F, Levade T. Significance of two point mutations present in each HEXB allele of patients with adult GM2 gangliosidosis (Sandhoff disease) homozygosity for the Ile207-->Val substitution is not associated with a clinical or biochemical phenotype. Biochim Biophys Acta. 1996 Nov 15;1317(2):127-33. PMID:8950198
- ↑ Narkis G, Adam A, Jaber L, Pennybacker M, Proia RL, Navon R. Molecular basis of heat labile hexosaminidase B among Jews and Arabs. Hum Mutat. 1997;10(6):424-9. PMID:9401004 doi:<424::AID-HUMU2>3.0.CO;2-D 10.1002/(SICI)1098-1004(1997)10:6<424::AID-HUMU2>3.0.CO;2-D
- ↑ Fujimaru M, Tanaka A, Choeh K, Wakamatsu N, Sakuraba H, Isshiki G. Two mutations remote from an exon/intron junction in the beta-hexosaminidase beta-subunit gene affect 3'-splice site selection and cause Sandhoff disease. Hum Genet. 1998 Oct;103(4):462-9. PMID:9856491
- ↑ Hou Y, McInnes B, Hinek A, Karpati G, Mahuran D. A Pro504 --> Ser substitution in the beta-subunit of beta-hexosaminidase A inhibits alpha-subunit hydrolysis of GM2 ganglioside, resulting in chronic Sandhoff disease. J Biol Chem. 1998 Aug 14;273(33):21386-92. PMID:9694901
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