2gk1

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[[Image:2gk1.gif|left|200px]]<br /><applet load="2gk1" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2gk1.gif|left|200px]]
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caption="2gk1, resolution 3.25&Aring;" />
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'''X-ray crystal structure of NGT-bound HexA'''<br />
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{{Structure
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|PDB= 2gk1 |SIZE=350|CAPTION= <scene name='initialview01'>2gk1</scene>, resolution 3.25&Aring;
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|SITE=
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|LIGAND= <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>
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|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]
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|GENE=
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}}
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'''X-ray crystal structure of NGT-bound HexA'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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2GK1 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NGT:'>NGT</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=2GK1 OCA].
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2GK1 is a [[Protein complex]] structure of sequences 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=2GK1 OCA].
==Reference==
==Reference==
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Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis., Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN, J Mol Biol. 2006 Jun 16;359(4):913-29. Epub 2006 Apr 27. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16698036 16698036]
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Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis., Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN, J Mol Biol. 2006 Jun 16;359(4):913-29. Epub 2006 Apr 27. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16698036 16698036]
[[Category: Beta-N-acetylhexosaminidase]]
[[Category: Beta-N-acetylhexosaminidase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Withers, S G.]]
[[Category: Withers, S G.]]
[[Category: NGT]]
[[Category: NGT]]
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[[Category: beta-hexoasaminidase a]]
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[[Category: beta-hexoasaminidase some]]
[[Category: glycosidase]]
[[Category: glycosidase]]
[[Category: gm2 gangliodosis]]
[[Category: gm2 gangliodosis]]
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[[Category: tay-sachs disease]]
[[Category: tay-sachs disease]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:32:27 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:05:36 2008''

Revision as of 15:05, 20 March 2008


PDB ID 2gk1

Drag the structure with the mouse to rotate
, resolution 3.25Å
Ligands:
Activity: Beta-N-acetylhexosaminidase, with EC number 3.2.1.52
Coordinates: save as pdb, mmCIF, xml



X-ray crystal structure of NGT-bound HexA


Contents

Overview

Lysosomal beta-hexosaminidase A (Hex A) is essential for the degradation of GM2 gangliosides in the central and peripheral nervous system. Accumulation of GM2 leads to severely debilitating neurodegeneration associated with Tay-Sachs disease (TSD), Sandoff disease (SD) and AB variant. Here, we present the X-ray crystallographic structure of Hex A to 2.8 A resolution and the structure of Hex A in complex with NAG-thiazoline, (NGT) to 3.25 A resolution. NGT, a mechanism-based inhibitor, has been shown to act as a chemical chaperone that, to some extent, prevents misfolding of a Hex A mutant associated with adult onset Tay Sachs disease and, as a result, increases the residual activity of Hex A to a level above the critical threshold for disease. The crystal structure of Hex A reveals an alphabeta heterodimer, with each subunit having a functional active site. Only the alpha-subunit active site can hydrolyze GM2 gangliosides due to a flexible loop structure that is removed post-translationally from beta, and to the presence of alphaAsn423 and alphaArg424. The loop structure is involved in binding the GM2 activator protein, while alphaArg424 is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. The beta-subunit lacks these key residues and has betaAsp452 and betaLeu453 in their place; the beta-subunit therefore cleaves only neutral substrates efficiently. Mutations in the alpha-subunit, associated with TSD, and those in the beta-subunit, associated with SD are discussed. The effect of NGT binding in the active site of a mutant Hex A and its effect on protein function is discussed.

Disease

Known diseases associated with this structure: GM2-gangliosidosis, several forms OMIM:[606869], Hex A pseudodeficiency OMIM:[606869], Sandhoff disease, infantile, juvenile, and adult forms OMIM:[606873], Spinal muscular atrophy, juvenile OMIM:[606873], Tay-Sachs disease OMIM:[606869]

About this Structure

2GK1 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis., Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN, J Mol Biol. 2006 Jun 16;359(4):913-29. Epub 2006 Apr 27. PMID:16698036

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