Protein 3Dpol, RNA dependent RNA polymerase, is a key enzyme for the life cycle of a + RNA viruses. The 3Dpol enzymes catalyze formation of phosphodiester bond between RNA nucleotides. The first residue of 3Dpol proteins is burned inside the protein. The correct protein folding of the N termini is the first residue dependent. The very first glycine is conserved among all the picornavirus except for kobuviruses (i. e. Aichi virus)- kobuviruses have a serine residue instead. Intrigued by this anomaly we sought to solve the crystal structure of kobuviral 3Dpol enzyme.
We determined the crystal structure of Aichi 3Dpol at 2.3 Å resolution. The structure uncovered an overall conserved fold of right hand. But the structure also revealed a unique fold of the 3Dpol N-termini, however, the very first serine residue is also inserted into a charged pocket via a water bridge suggesting that throughout the evolution of picornaviruses the mechanism of 3Dpol activation after precursor cleavage remains conserved.
The work was was supported by Czech Science Foundation grant number 17-05200S and also from European Regional Development Fund; OP RDE; Project: "Chemical biology for drugging undruggable targets (ChemBioDrug)" (No. CZ.02.1.01/0.0/0.0/16_019/