id7b00053_si_001.pdf (710.34 kB)
Allosteric Regulation of Phosphatidylinositol 4‑Kinase III Beta by an Antipicornavirus Compound MDL-860
journal contribution
posted on 2017-06-12, 00:00 authored by Minetaro Arita, Georgi Dobrikov, Gerhard Pürstinger, Angel S. GalabovMDL-860 is a broad-spectrum antipicornavirus
compound discovered
in 1982 and one of the few promising candidates effective in in vivo virus infection. Despite the effectiveness, the
target and the mechanism of action of MDL-860 remain unknown. Here,
we have characterized antipoliovirus activity of MDL-860 and identified
host phosphatidylinositol-4 kinase III beta (PI4KB) as the target.
MDL-860 treatment caused covalent modification and irreversible inactivation
of PI4KB. A cysteine residue at amino acid 646 of PI4KB, which locates
at the bottom of a surface pocket apart from the active site, was
identified as the target site of MDL-860. This work reveals the mechanism
of action of this class of PI4KB inhibitors and offers insights into
novel allosteric regulation of PI4KB activity.