Ma, Xiaolei, Xie, Lili, Wartchow, Charles, Warne, Robert, Rivkin, Alexey, Tully, David, Shia, Steven, Uehara, Kyoko, Muiru, Gladys, Zhong, Weidong, Zaror, Isabel, Bussiere, Dirksen, Leonard, Vincent and Baldwin, Dianna (2017) Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit. Scientific reports.

Abstract

Influenza virus uses a unique mechanism to initiate viral transcription named cap-snatching. The PB2 subunit of the viral heterotrimeric RNA polymerase binds the cap structure of cellular pre-mRNA to promote its cleavage by the PA subunit. The resulting 11-13 capped oligomer is used by the PB1 polymerase subunit to initiate transcription of viral proteins. VX-787 is an inhibitor of the influenza A virus pre-mRNA cap-binding protein PB2. This clinical stage compound was shown to bind the minimal cap-binding domain of PB2 to inhibit the cap-snatching machinery. However, the binding of this molecule in the context of an extended form of the PB2 subunit has remained elusive. Here we generated a collection of PB2 truncations to identify a PB2 protein representative of its structure in the viral heterotrimeric protein. We present the crystal structure of VX-787 bound to a PB2 construct that recapitulates VX-787's biological antiviral activity in vitro. This co-structure reveals more extensive interactions than previously identified and provides insight into the observed resistance profile, affinity, binding kinetics, and conformational rearrangements induced by VX-787.

Item Type:	Article
Date Deposited:	02 Jan 2018 00:45
Last Modified:	02 Jan 2018 00:45
URI:	https://oak.novartis.com/id/eprint/33141