1vcu

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spinqualitylabelsall models 1vcu, resolution 2.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Structure of the human cytosolic sialidase Neu2 in complex with the inhibitor DANA

Overview

Gangliosides play key roles in cell differentiation, cell-cell, interactions, and transmembrane signaling. Sialidases hydrolyze sialic, acids to produce asialo compounds, which is the first step of degradation, processes of glycoproteins and gangliosides. Sialidase involvement has, been implicated in some lysosomal storage disorders such as sialidosis and, galactosialidosis. Neu2 is a recently identified human cytosolic, sialidase. Here we report the first high resolution x-ray structures of, mammalian sialidase, human Neu2, in its apo form and in complex with an, inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA). The, structure shows the canonical six-blade beta-propeller observed in viral, and bacterial sialidases with its active site in a shallow crevice. In the, complex structure, the inhibitor lies in the catalytic crevice surrounded, by ten amino acids. In particular, the arginine triad, conserved among, sialidases, aids in the proper positioning of the carboxylate group of, DANA within the active site region. The tyrosine residue, Tyr(334), conserved among mammalian and bacterial sialidases as well as in viral, neuraminidases, facilitates the enzymatic reaction by stabilizing a, putative carbonium ion in the transition state. The loops containing, Glu(111) and the catalytic aspartate Asp(46) are disordered in the apo, form but upon binding of DANA become ordered to adopt two short, alpha-helices to cover the inhibitor, illustrating the dynamic nature of, substrate recognition. The N-acetyl and glycerol moieties of DANA are, recognized by Neu2 residues not shared by bacterial sialidases and viral, neuraminidases, which can be regarded as a key structural difference for, potential drug design against bacteria, influenza, and other viruses.

About this Structure

1VCU is a Single protein structure of sequence from Homo sapiens with DAN and EPE as ligands. Active as Exo-alpha-sialidase, with EC number 3.2.1.18 Full crystallographic information is available from OCA.

Reference

Crystal structure of the human cytosolic sialidase Neu2. Evidence for the dynamic nature of substrate recognition., Chavas LM, Tringali C, Fusi P, Venerando B, Tettamanti G, Kato R, Monti E, Wakatsuki S, J Biol Chem. 2005 Jan 7;280(1):469-75. Epub 2004 Oct 22. PMID:15501818

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