Structure of the foot-and-mouth disease virus leader protease: a papain-like fold adapted for self-processing and eIF4G recognition

The leader protease of foot-and-mouth disease virus, as well as cleaving it self from the nascent viral polyprotein, disables host cell protein synthes is by specific proteolysis of a cellular protein: the eukaryotic initiation factor 4G (eIF4G), The crystal structure of the leader protease presented here comprises a globular catalytic domain reminiscent of that of cysteine proteases of the papain superfamily, and a flexible C-terminal extension fo und intruding into the substrate-binding site of an adjacent molecule, Neve rtheless, the relative disposition of this extension and the globular domai n to each other supports intramolecular self-processing. The different sequ ences of the two substrates cleaved during viral replication, the viral pol yprotein (at LysLeuLys down arrow GlyAlaGly) and eIF4G (at AsnLeuGly down a rrow ArgThrThr), appear to be recognized by distinct features in a narrow n egatively charged groove traversing the active centre, The structure illust rates how the prototype papain fold has been adapted to the requirements of an RNA virus, Thus, the protein scaffold has been reduced to a minimum cor e domain, with the active site being modified to increase specificity, Furt hermore, surface features have been developed which enable C-terminal self- processing from the viral polyprotein.