Senecavirus A (SVA) is an emerging picornavirus infecting porcine of all age groups and causing foot and mouth disease (FMD)-like symptoms. One of its key enzymes is the 3C protease (3C^pro), which is similar to other picornaviruses and essential for virus maturation by controlling polyprotein cleavage and RNA replication. In this study, we reported the crystal structure of SVA 3C^pro at a resolution of 1.9 Å and a thorough structural comparison against all published picornavirus 3C^pro structures. Using statistical and graphical visualization techniques, we also investigated the sequence specificity of the 3C^pro. The structure revealed that SVA 3C^pro adopted a typical chymotrypsin-like fold with the S1 subsite as the most conservative site among picornavirus 3C^pro. The surface loop, A1-B1 hairpin, adopted a novel conformation in SVA 3C^pro and formed a positively charged protrusion around S' subsites. Correspondingly, SVA scissile bonds preferred Asp rather than neutral amino acids at P3' and P4'. Moreover, SVA 3C^pro showed a wide range tolerance to P4 residue volume (acceptable range: 67 Å³ to 141 Å³), such as aromatic side chain, in contrast to other picornaviruses. In summary, our results provided valuable information for understanding the cleavage pattern of 3C^pro. IMPORTANCE Picornaviridae is a group of RNA viruses that harm both humans and livestock. 3C^pro is an essential enzyme for picornavirus maturation, which makes it a promising target for antiviral drug development and a critical component for virus-like particle (VLP) production. However, the current challenge in the development of antiviral drugs and VLP vaccines includes the limited knowledge of how subsite structure determines the 3C^pro cleavage pattern. Thus, an extensive comparative study of various picornaviral 3C^pro was required. Here, we showed the 1.9 Å crystal structure of SVA 3C^pro. The structure revealed similarities and differences in the substrate-binding groove among picornaviruses, providing new insights into the development of inhibitors and VLP.

#	Concept	H-Index	Publications	Citations
1	Engineering	1	1	17
2	Applied Physics	1	1	17
3	Electrical Engineering	1	1	17
4	Materials Science	1	1	17
5	Electrochemistry	1	1	17

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