PDBsum entry 5wb3

Hydrolase/hydrolase inhibitor

PDB id: 5wb3

Contents

Protein chain

180 a.a.

Ligands

SO4 ×2

GYA

Metals

_MN ×2

Waters ×16

PDB id:

5wb3

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of the influenza virus pa endonuclease in complex with inhibitor 10j (sri-30026)

Structure:

Polymerase acidic protein. Chain: a. Engineered: yes

Source:

Influenza a virus. Organism_taxid: 641501. Strain: swl a/california/04/2009 h1n1. Gene: pa. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.20Å R-factor: 0.217 R-free: 0.242

Authors:

G.Kumar,S.W.White

Key ref:

D.Beylkin et al. (2017). Protein-Structure Assisted Optimization of 4,5-Dihydroxypyrimidine-6-Carboxamide Inhibitors of Influenza Virus Endonuclease. Sci Rep, 7, 17139. PubMed id: 29215062

Date:

27-Jun-17 Release date: 03-Jan-18

Protein chain

C3W5S0  (PA_I09A0) -  Polymerase acidic protein from Influenza A virus (strain swl A/California/04/2009 H1N1)

Seq: 716 a.a.

Struc: 180 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.1.-.-

Sci Rep 7:17139 (2017)

PubMed id: 29215062

Protein-Structure Assisted Optimization of 4,5-Dihydroxypyrimidine-6-Carboxamide Inhibitors of Influenza Virus Endonuclease.

D.Beylkin, G.Kumar, W.Zhou, J.Park, T.Jeevan, C.Lagisetti, R.Harfoot, R.J.Webby, S.W.White, T.R.Webb.

ABSTRACT

Influenza is a serious hazard to human health that causes hundreds of thousands of deaths annually. Though vaccines and current therapeutics can blunt some of the perilous impact of this viral infection, new treatments are needed due to the constantly evolving nature of this virus. Recently, our growing understanding of an essential influenza viral protein, PA, has led to the development of focused libraries of new small molecules that specifically target the active site of the PA influenza endonuclease, which we report here. Our overarching approach has been to proactively develop lead inhibitors that are less likely to rapidly develop clinical resistance by optimizing inhibitors that retain activity against induced resistant mutants. Here, we report details behind the discovery of new potent inhibitors of wild type and resistant mutant endonucleases along with their high-resolution co-crystal structure-activity relationships. These results add to our understanding of nuclease protein targets and potentially serve as starting points for a new therapeutic approach to the treatment of influenza.