4AWF

Influenza strain pH1N1 2009 polymerase subunit PA endonuclease in complex with 2 4-dioxo-4-phenylbutanoic acid DPBA

Summary for 4AWF

• Entry DOI: 10.2210/pdb4awf/pdb
• Related: 4AVG 4AVL 4AVQ 4AWG 4AWH 4AWK 4AWM
• Descriptor: POLYMERASE PA, MANGANESE (II) ION, 2-4-DIOXO-4-PHENYLBUTANOIC ACID, ... (4 entities in total)
• Functional Keywords: hydrolase-inhibitor complex, hydrolase, manganese-dependent, hydrolase/inhibitor
• Biological source: INFLUENZA A VIRUS
• Total number of polymer chains: 4
• Total formula weight: 96965.34

Authors

Kowalinski, E.,Zubieta, C.,Wolkerstorfer, A.,Szolar, O.H.,Ruigrok, R.W.,Cusack, S. (deposition date: 2012-06-03, release date: 2012-08-22, Last modification date: 2023-12-20)

Primary citation

Kowalinski, E.,Zubieta, C.,Wolkerstorfer, A.,Szolar, O.H.,Ruigrok, R.W.,Cusack, S.
Structural Analysis of Specific Metal Chelating Inhibitor Binding to the Endonuclease Domain of Influenza Ph1N1 (2009) Polymerase.
Plos Pathog., 8:2831-, 2012

PubMed Abstract: It is generally recognised that novel antiviral drugs, less prone to resistance, would be a desirable alternative to current drug options in order to be able to treat potentially serious influenza infections. The viral polymerase, which performs transcription and replication of the RNA genome, is an attractive target for antiviral drugs since potent polymerase inhibitors could directly stop viral replication at an early stage. Recent structural studies on functional domains of the heterotrimeric polymerase, which comprises subunits PA, PB1 and PB2, open the way to a structure based approach to optimise inhibitors of viral replication. In particular, the unique cap-snatching mechanism of viral transcription can be inhibited by targeting either the PB2 cap-binding or PA endonuclease domains. Here we describe high resolution X-ray co-crystal structures of the 2009 pandemic H1N1 (pH1N1) PA endonuclease domain with a series of specific inhibitors, including four diketo compounds and a green tea catechin, all of which chelate the two critical manganese ions in the active site of the enzyme. Comparison of the binding mode of the different compounds and that of a mononucleotide phosphate highlights, firstly, how different substituent groups on the basic metal binding scaffold can be orientated to bind in distinct sub-pockets within the active site cavity, and secondly, the plasticity of certain structural elements of the active site cavity, which result in induced fit binding. These results will be important in optimising the design of more potent inhibitors targeting the cap-snatching endonuclease activity of influenza virus polymerase.

PubMed: 22876177
DOI: 10.1371/JOURNAL.PPAT.1002831

Experimental method

X-RAY DIFFRACTION (2.3 Å)