2gk1
From Proteopedia
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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 with NGT as ligand. Active as Beta-N-acetylhexosaminidase, with EC number 3.2.1.52 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
Page seeded by OCA on Mon Nov 12 22:19:33 2007