THE STRUCTURES OF SALMONELLA-TYPHIMURIUM LT2 NEURAMINIDASE AND ITS COMPLEXES WITH 3 INHIBITORS AT HIGH-RESOLUTION

The structure of Salmonella typhimurium LT2 neuraminidase (STNA) is re ported here to a resolution of 1.6 Angstrom together with the structur es of three complexes of STNA with different inhibitors. The first is 2-deoxy-2,3-dehydro-N-acetyl-neuraminic acid (Neu5Ac2en or DANA), the second and third are phosphonate derivatives of N-acetyl-neuraminic ac id (NANA) which have phosphonate groups at the C2 position equatorial (ePANA) and axial (aPANA) to the plane of the sugar ring. The complex structures are at resolutions of 1.6 Angstrom, 1.6 Angstrom and 1.9 An gstrom, respectively. These analyses show the STNA active site to be t opologically inflexible and the interactions to be dominated by the ar ginine triad, with the pyranose rings of the inhibitors undergoing dis tortion to occupy the space available. Solvent structure differs only around the third phosphonate oxygen, which attracts a potassium ion. T he STNA structure is topologically identical to the previously reporte d influenza virus neuraminidase structures, although very different in detail; the root-mean-square (r.m.s.) deviation for 210 C-alpha posit ions considered equivalent is 2.28 Angstrom (out of a total of 390 res idues in influenza and 381 in STNA). The active site residues are more highly conserved, in that both the viral and bacterial structures con tain an arginine triad, a hydrophobic pocket, a tyrosine and a glutami c acid residue at the base of the site and a potential proton-donating aspartic acid. However, differences in binding to O4 and to the glyce rol side-chain may reflect the different kinetics employed by the two enzymes. (C) 1996 Academic Press Limited