Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor
|Authors:||Lei J, Hansen G, Nitsche C, Klein CD, Zhang L, Hilgenfeld R|
|CellNetworks People:||Klein Christian|
|Journal:||Science. 2016 Jul 29;353(6298):503-5. doi: 10.1126/science.aag2419|
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 angstrom; 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 nonconserved Asp(83) of NS2B; ion-pairing between Asp(83) 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.