3W95

Crystal structure of 2A proteinase (C110A) from enterovirus 71

Summary for 3W95

• Entry DOI: 10.2210/pdb3w95/pdb
• Related: 1z8r 2hrv
• Descriptor: Genome polyprotein, ZINC ION (3 entities in total)
• Functional Keywords: chymotrypsin-fold six-stranded beta-barrel catalytic triad zinc-coordination, chymotrypsin-fold six-stranded beta-barrel catalytic triad, hydrolase
• Biological source: Human enterovirus 71 (Ev 71)
• Total number of polymer chains: 1
• Total formula weight: 18930.39

Authors

Mu, Z.,Gao, X.,Cui, S. (deposition date: 2013-03-27, release date: 2013-09-04, Last modification date: 2023-11-08)

Primary citation

Mu, Z.,Wang, B.,Zhang, X.,Gao, X.,Qin, B.,Zhao, Z.,Cui, S.
Crystal Structure of 2A Proteinase from Hand, Foot and Mouth Disease Virus
J.Mol.Biol., 425:4530-4543, 2013

PubMed Abstract: EV71 is responsible for several epidemics worldwide; however, the effective antiviral drug is unavailable to date. The 2A proteinase (2A(pro)) of EV71 presents a promising drug target due to its multiple roles in virus replication, inhibition of host protein synthesis and evasion of innate immunity. We determined the crystal structure of EV71 2A(pro) at 1.85Å resolution, revealing that the proteinase maintains a chymotrypsin-like fold. The active site is composed of the catalytic triads C110A, H21 and D39 with the geometry similar to that in other picornaviral 2A(pro), 3C(pro) and serine proteinases. The cI-to-eI2 loop at the N-terminal domain of EV71 2A(pro) adopts a highly stable conformation and contributes to the hydrophilic surface property, which are strikingly different in HRV2 2A(pro) but are similar in CVB4 2A(pro). We identified a hydrophobic motif "LLWL" followed by an acidic motif "DEE" at the C-terminus of EV71 2A(pro). The "LLWL" motif is folded into the β-turn structure that is essential for the positioning of the acidic motif. Our structural and mutagenesis study demonstrated that both the negative charging and the correct positioning of the C-terminus are essential for EV71 replication. Deletion of the "LLWL" motif abrogated the proteolytic activity, indicating that the motif is critical for maintaining the active proteinase conformation. Our findings provide the structural and functional insights into EV71 2A(pro) and establish a framework for structure-based inhibitor design.

PubMed: 23973886
DOI: 10.1016/j.jmb.2013.08.016

Experimental method

X-RAY DIFFRACTION (1.85 Å)