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PDBsum entry 4m5o

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protein ligands metals links
RNA binding protein/inhibitor PDB id
4m5o
Jmol
Contents
Protein chain
200 a.a.
Ligands
SO4
EDO
X48 ×3
Metals
_MN ×3
Waters ×139
PDB id:
4m5o
Name: RNA binding protein/inhibitor
Title: 3-hydroxy-6-phenyl-1,2-dihydropyridin-2-one bound to influen h1n1 endonuclease
Structure: Polymerase pa. Chain: a. Fragment: unp residues 1-204. Engineered: yes
Source: Influenza a virus (a/lima/wrair1695p/2009(h1n1)). Organism_taxid: 985958. Gene: pa. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.00Å     R-factor:   0.184     R-free:   0.218
Authors: J.D.Bauman,D.Patel,K.Das,E.Arnold
Key ref: J.D.Bauman et al. (2013). Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors. ACS Chem Biol, 8, 2501-2508. PubMed id: 23978130 DOI: 10.1021/cb400400j
Date:
08-Aug-13     Release date:   18-Sep-13    
PROCHECK
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 Headers
 References

Protein chain
Pfam  
F0TRT1  (F0TRT1_9INFA) - 
Key:    Secondary structure

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     transcription, DNA-dependent   1 term 
  Biochemical function     RNA binding     2 terms  

 

 
DOI no: 10.1021/cb400400j ACS Chem Biol 8:2501-2508 (2013)
PubMed id: 23978130  
 
 
Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors.
J.D.Bauman, D.Patel, S.F.Baker, R.S.Vijayan, A.Xiang, A.K.Parhi, L.Martínez-Sobrido, E.J.LaVoie, K.Das, E.Arnold.
 
  ABSTRACT  
 
Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance to the current drugs and the variable efficacy of vaccines underscore the need for developing new flu drugs that will be broadly effective against wild-type and drug-resistant influenza strains. Here, we report the discovery and development of a class of inhibitors targeting the cap-snatching endonuclease activity of the viral polymerase. A high-resolution crystal form of pandemic 2009 H1N1 influenza polymerase acidic protein N-terminal endonuclease domain (PAN) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PAN active site cleft. During the course of screening, binding of a third metal ion that is potentially relevant to endonuclease activity was detected in the active site cleft of PAN in the presence of a fragment. Using structure-based optimization, we developed a highly potent hydroxypyridinone series of compounds from a fragment hit that defines a new mode of chelation to the active site metal ions. A compound from the series demonstrating promising enzymatic inhibition in a fluorescence-based enzyme assay with an IC50 value of 11 nM was found to have an antiviral activity (EC50) of 11 μM against PR8 H1N1 influenza A in MDCK cells.