5WL0

Co-crystal structure of Influenza A H3N2 PB2 (241-741) bound to VX-787

Summary for 5WL0

• Entry DOI: 10.2210/pdb5wl0/pdb
• Descriptor: Polymerase basic protein 2, (2S,3S)-3-[[5-fluoranyl-2-(5-fluoranyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylic acid, DI(HYDROXYETHYL)ETHER, ... (4 entities in total)
• Functional Keywords: polymerase basic protein 2, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Influenza A virus (strain A/Udorn/307/1972 H3N2)
• Cellular location: Virion : Q67296
• Total number of polymer chains: 1
• Total formula weight: 58090.48

Authors

Ma, X.,Shia, S. (deposition date: 2017-07-25, release date: 2017-09-06, Last modification date: 2023-10-04)

Primary citation

Ma, X.,Xie, L.,Wartchow, C.,Warne, R.,Xu, Y.,Rivkin, A.,Tully, D.,Shia, S.,Uehara, K.,Baldwin, D.M.,Muiru, G.,Zhong, W.,Zaror, I.,Bussiere, D.E.,Leonard, V.H.J.
Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit.
Sci Rep, 7:9385-9385, 2017

PubMed 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.

PubMed: 28839261
DOI: 10.1038/s41598-017-09538-x

Experimental method

X-RAY DIFFRACTION (2.4 Å)