Crystal structure of unlinked NS2B-NS3 protease from Zika virus

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Science  23 Dec 2016:
Vol. 354, Issue 6319, pp. 1597-1600
DOI: 10.1126/science.aai9309

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A closed conformation for Zika virus enzyme

The recent Zika virus epidemic highlights the need for antiviral drugs. One important drug target is the virus's NS2B-NS3 protease, an enzyme that is critical for viral replication. Zhang et al. report high-resolution crystal structures of the protease as a free enzyme and with a peptide bound to the active site in the reverse position. The structures reveal that, unlike in other flaviviruses, the protease adopts a closed conformation, in which NS2B engages NS3 to form the empty substrate-binding site. Moreover, substrate binding did not substantially alter the conformation of the enzyme.

Science, this issue p. 1597


Zika virus (ZIKV) has rapidly emerged as a global public health concern. Viral NS2B-NS3 protease processes viral polyprotein and is essential for the virus replication, making it an attractive antiviral drug target. We report crystal structures at 1.58-angstrom resolution of the unlinked NS2B-NS3 protease from ZIKV as free enzyme and bound to a peptide reversely oriented at the active site. The unlinked NS2B-NS3 protease adopts a closed conformation in which NS2B engages NS3 to form an empty substrate-binding site. A second protease in the same crystal binds to the residues K14K15G16E17 from the neighboring NS3 in reverse orientation, resisting proteolysis. These features of ZIKV NS2B-NS3 protease may accelerate the discovery of structure-based antiviral drugs against ZIKV and related pathogenic flaviviruses.

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