Abstract
The crystal structure of 3C proteinase (3C(pro)) from Enterovirus 71 (EV71) was determined in space group C2221 to 2.2 Å resolution. The fold was similar to that of 3C(pro) from other picornaviruses, but the difference in the β-ribbon reported in a previous structure was not observed. This β-ribbon was folded over the substrate-binding cleft and constituted part of the essential binding sites for interaction with the substrate. The structure of its complex with rupintrivir (AG7088), a peptidomimetic inhibitor, was also characterized in space group P212121 to 1.96 Å resolution. The inhibitor was accommodated without any spatial hindrance despite the more constricted binding site; this was confirmed by functional assays, in which the inhibitor showed comparable potency towards EV71 3C(pro) and human rhinovirus 3C(pro), which is the target that rupintrivir was designed against.
Keywords:
3C proteinases; EV71; Enterovirus; drug design; hand, foot and mouth disease; rupintrivir.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3C Viral Proteases
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Amino Acid Sequence
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Antiviral Agents / chemistry*
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Antiviral Agents / pharmacology
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Binding Sites
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Catalytic Domain
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Cell Line / drug effects
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Cell Line / virology
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Conserved Sequence
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Crystallography, X-Ray
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Cysteine Endopeptidases / chemistry*
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / pharmacology
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Enterovirus A, Human / enzymology*
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Humans
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Isoxazoles / chemistry*
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Isoxazoles / metabolism
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Isoxazoles / pharmacology
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Models, Molecular
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Molecular Sequence Data
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Phenylalanine / analogs & derivatives
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Protein Conformation
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Pyrrolidinones / chemistry*
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Pyrrolidinones / metabolism
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Pyrrolidinones / pharmacology
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Valine / analogs & derivatives
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Viral Proteins / antagonists & inhibitors
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Viral Proteins / chemistry*
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Viral Proteins / metabolism*
Substances
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Antiviral Agents
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Cysteine Proteinase Inhibitors
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Isoxazoles
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Pyrrolidinones
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Viral Proteins
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Phenylalanine
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Cysteine Endopeptidases
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3C Viral Proteases
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Valine
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rupintrivir