3SJ9

crystal structure of the C147A mutant 3C of CVA16 in complex with FAGLRQAVTQ peptide

Summary for 3SJ9

• Entry DOI: 10.2210/pdb3sj9/pdb
• Related: 1CQQ 1L1N 2ZTY 3SJ8 3SJI 3SJK 3SJO
• Descriptor: 3C protease, FAGLRQAVTQ peptide (3 entities in total)
• Functional Keywords: binding to its substrate-peptide, chymotrypsin-like fold, protease, hydrolase
• Biological source: Human coxsackievirus A16
• Total number of polymer chains: 2
• Total formula weight: 22149.36

Authors

Lu, G.,Qi, J.,Chen, Z.,Xu, X.,Gao, F.,Lin, D.,Qian, W.,Liu, H.,Jiang, H.,Yan, J.,Gao, G.F. (deposition date: 2011-06-21, release date: 2011-08-10, Last modification date: 2023-09-13)

Primary citation

Lu, G.,Qi, J.,Chen, Z.,Xu, X.,Gao, F.,Lin, D.,Qian, W.,Liu, H.,Jiang, H.,Yan, J.,Gao, G.F.
Enterovirus 71 and Coxsackievirus A16 3C Proteases: Binding to Rupintrivir and Their Substrates and Anti-Hand, Foot, and Mouth Disease Virus Drug Design.
J.Virol., 85:10319-10331, 2011

PubMed Abstract: Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the major causative agents of hand, foot, and mouth disease (HFMD), which is prevalent in Asia. Thus far, there are no prophylactic or therapeutic measures against HFMD. The 3C proteases from EV71 and CVA16 play important roles in viral replication and are therefore ideal drug targets. By using biochemical, mutational, and structural approaches, we broadly characterized both proteases. A series of high-resolution structures of the free or substrate-bound enzymes were solved. These structures, together with our cleavage specificity assay, well explain the marked substrate preferences of both proteases for particular P4, P1, and P1' residue types, as well as the relative malleability of the P2 amino acid. More importantly, the complex structures of EV71 and CVA16 3Cs with rupintrivir, a specific human rhinovirus (HRV) 3C protease inhibitor, were solved. These structures reveal a half-closed S2 subsite and a size-reduced S1' subsite that limit the access of the P1' group of rupintrivir to both enzymes, explaining the reported low inhibition activity of the compound toward EV71 and CVA16. In conclusion, the detailed characterization of both proteases in this study could direct us to a proposal for rational design of EV71/CVA16 3C inhibitors.

PubMed: 21795339
DOI: 10.1128/JVI.00787-11

Experimental method

X-RAY DIFFRACTION (2.399 Å)