PDBsum entry 6e4c

Hydrolase/hydrolase inhibitor

PDB id: 6e4c

Contents

Protein chain

176 a.a.

Ligands

HRJ

EDO

Metals

_MN ×2

Waters ×32

PDB id:

6e4c

Name:

Hydrolase/hydrolase inhibitor

Title:

The n-terminal domain of pa endonuclease from the influenza h1n1 virus in complex with 3-hydroxy-6-(2-methyl-4-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)phenyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid

Structure:

Polymerase acidic protein. Chain: a. Fragment: n-terminal domain (unp residues 1-198). Synonym: RNA-directed RNA polymerase subunit p2. Engineered: yes

Source:

Influenza a virus. Organism_taxid: 641501. Strain: swl a/california/04/2009 h1n1. Gene: pa. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693

Resolution:

2.35Å R-factor: 0.200 R-free: 0.260

Authors:

C.N.Morrison,B.L.Dick,C.V.Credille,S.M.Cohen

Key ref:

C.V.Credille et al. (2019). SAR Exploration of Tight-Binding Inhibitors of Influenza Virus PA Endonuclease. J Med Chem, 62, 9438-9449. PubMed id: 31536340 DOI: 10.1021/acs.jmedchem.9b00747

Date:

17-Jul-18 Release date: 17-Jul-19

Protein chain

C3W5S0  (C3W5S0_I09A0) -  Polymerase acidic protein from Influenza A virus (strain swl A/California/04/2009 H1N1)

Seq: 716 a.a.

Struc: 176 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.3.1.-.-

DOI no: 10.1021/acs.jmedchem.9b00747

J Med Chem 62:9438-9449 (2019)

PubMed id: 31536340

SAR Exploration of Tight-Binding Inhibitors of Influenza Virus PA Endonuclease.

C.V.Credille, C.N.Morrison, R.W.Stokes, B.L.Dick, Y.Feng, J.Sun, Y.Chen, S.M.Cohen.

ABSTRACT

Significant efforts have been reported on the development of influenza antivirals including inhibitors of the RNA-dependent RNA polymerase PA N-terminal (PA_N) endonuclease. Based on recently identified, highly active metal-binding pharmacophores (MBPs) for PA_N endonuclease inhibition, a fragment-based drug development campaign was pursued. Guided by coordination chemistry and structure-based drug design, MBP scaffolds were elaborated to improve activity and selectivity. Structure-activity relationships were established and used to generate inhibitors of influenza endonuclease with tight-binding affinities. The activity of these inhibitors was analyzed using a fluorescence-quenching-based nuclease activity assay, and binding was validated using differential scanning fluorometry. Lead compounds were found to be highly selective for PA_N endonuclease against several related dinuclear and mononuclear metalloenzymes. Combining principles of bioinorganic and medicinal chemistry in this study has resulted in some of the most active in vitro influenza PA_N endonuclease inhibitors with high ligand efficiencies.