PDBsum entry 4zqq

Hydrolase

PDB id: 4zqq

Contents

Protein chain

181 a.a.

Ligands

SO4

Metals

_MN ×2

Waters ×237

PDB id:

4zqq

Name:

Hydrolase

Title:

Apo form of influenza strain h1n1 polymerase acidic subunit n-terminal region

Structure:

Polymerase acidic protein,polymerase acidic protein. Chain: a. Fragment: n-terminal region (unp residues 1-50, 73-197). Synonym: RNA-directed RNA polymerase subunit p2. Engineered: yes

Source:

Influenza a virus (strain a/puerto rico/8/1934 h1n1). Organism_taxid: 211044. Strain: a/puerto rico/8/1934 h1n1. Gene: pa. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.80Å R-factor: 0.226 R-free: 0.274

Authors:

S.Fudo,N.Yamamoto,M.Nukaga,T.Odagiri,M.Tashiro,S.Neya,T.Hoshino

Key ref:

S.Fudo et al. (2016). Two Distinctive Binding Modes of Endonuclease Inhibitors to the N-Terminal Region of Influenza Virus Polymerase Acidic Subunit. Biochemistry, 55, 2646-2660. PubMed id: 27088785 DOI: 10.1021/acs.biochem.5b01087

Date:

11-May-15 Release date: 03-Jun-15

Protein chain

P03433  (PA_I34A1) -  Polymerase acidic protein from Influenza A virus (strain A/Puerto Rico/8/1934 H1N1)

Seq: 716 a.a.

Struc: 181 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.1.-.-

DOI no: 10.1021/acs.biochem.5b01087

Biochemistry 55:2646-2660 (2016)

PubMed id: 27088785

Two Distinctive Binding Modes of Endonuclease Inhibitors to the N-Terminal Region of Influenza Virus Polymerase Acidic Subunit.

S.Fudo, N.Yamamoto, M.Nukaga, T.Odagiri, M.Tashiro, T.Hoshino.

ABSTRACT

Influenza viruses are global threat to humans, and the development of new antiviral agents are still demanded to prepare for pandemics and to overcome the emerging resistance to the current drugs. Influenza polymerase acidic protein N-terminal domain (PAN) has endonuclease activity and is one of the appropriate targets for novel antiviral agents. First, we performed X-ray cocrystal analysis on the complex structures of PAN with two endonuclease inhibitors. The protein crystallization and the inhibitor soaking were done at pH 5.8. The binding modes of the two inhibitors were different from a common binding mode previously reported for the other influenza virus endonuclease inhibitors. We additionally clarified the complex structures of PAN with the same two endonuclease inhibitors at pH 7.0. In one of the crystal structures, an additional inhibitor molecule, which chelated to the two metal ions in the active site, was observed. On the basis of the crystal structures at pH 7.0, we carried out 100 ns molecular dynamics (MD) simulations for both of the complexes. The analysis of simulation results suggested that the binding mode of each inhibitor to PAN was stable in spite of the partial deviation of the simulation structure from the crystal one. Furthermore, crystal structure analysis and MD simulation were performed for PAN in complex with an inhibitor, which was already reported to have a high compound potency for comparison. The findings on the presence of multiple binding sites at around the PAN substrate-binding pocket will provide a hint for enhancing the binding affinity of inhibitors.