1NOW

Human lysosomal beta-hexosaminidase isoform B in complex with (2R,3R,4S,5R)-2-Acetamido-3,4-Dihydroxy-5-Hydroxymethyl-Piperidinium Chloride (GalNAc-isofagomine)

Summary for 1NOW

• Entry DOI: 10.2210/pdb1now/pdb
• Related: 1NOU
• Descriptor: beta-hexosaminidase beta chain, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, (2R,3R,4S,5R)-2-ACETAMIDO-3,4-DIHYDROXY-5-HYDROXYMETHYL-PIPERIDINE, ... (6 entities in total)
• Functional Keywords: (beta/alpha)8-barrel, homodimer, family 20 glycosidase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 117999.35

Authors

Mark, B.L.,Mahuran, D.J.,Cherney, M.M.,Zhao, D.,Knapp, S.,James, M.N.G. (deposition date: 2003-01-16, release date: 2003-04-29, Last modification date: 2024-11-13)

Primary citation

Mark, B.L.,Mahuran, D.J.,Cherney, M.M.,Zhao, D.,Knapp, S.,James, M.N.G.
Crystal structure of Human beta-hexosaminidase B: Understanding the molecular basis of Sandhoff and Tay-Sachs disease
J.Mol.Biol., 327:1093-1109, 2003

PubMed Abstract: 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).

PubMed: 12662933
DOI: 10.1016/S0022-2836(03)00216-X

Experimental method

X-RAY DIFFRACTION (2.2 Å)