Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor

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Science  07 Jul 2016:
DOI: 10.1126/science.aag2419

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The ongoing Zika virus (ZIKV) outbreak is linked to severe neurological disorders. ZIKV relies on its NS2B/NS3 protease for polyprotein processing; hence, this enzyme is an attractive drug target. The 2.7 Å crystal structure of ZIKV protease in complex with a peptidomimetic boronic-acid inhibitor reveals a cyclic diester between the boronic acid and glycerol. The P2 4-aminomethylphenylalanine moiety of the inhibitor forms a salt-bridge with the non-conserved Asp83 of NS2B, Ion-pairing between Asp83 and the P2 residue of the substrate likely accounts for the enzyme's high catalytic efficiency. The unusual dimer of the ZIKV protease:inhibitor complex seen in the crystal may provide a model for assemblies formed at high local concentrations of protease at the endoplasmatic reticulum membrane, the site of polyprotein processing.

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