6YA5 | pdb_00006ya5

2009 H1N1 PA Endonuclease in complex with LU2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 
    0.264 (Depositor), 0.260 (DCC) 
  • R-Value Work: 
    0.202 (Depositor), 0.210 (DCC) 
  • R-Value Observed: 
    0.205 (Depositor) 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Beyond natural flavonoids: exploring bioisosterism in design and synthesis of influenza endonuclease inhibitors.

Reiberger, R.Kral, M.Radilova, K.Kotacka, T.Dracinsky, M.Tsalyy, A.Brynda, J.Majer, P.Konvalinka, J.Kozisek, M.Machara, A.

(2025) RSC Med Chem 

  • DOI: https://doi.org/10.1039/d5md00071h
  • Primary Citation of Related Structures:  
    6YA5, 8PPX

  • PubMed Abstract: 

    Influenza virus, an RNA virus of the Orthomyxoviridae family, is responsible for widespread seasonal epidemics that result in 3 to 5 million severe illnesses and more than half a million deaths annually. Given the persistent circulation of pandemic influenza variants and increasing resistance to available inhibitors, there is an urgent need for new antiviral drugs effective against various viral subtypes. Viral RNA-dependent RNA polymerase, essential for viral replication, has emerged as a promising drug target. The PA subunit with endonuclease function is especially interesting, as development of the highly potent baloxavir marboxil (Xofluza) validated its importance as a novel drug target. Flavonoids have long been studied for their anti-influenza activity but have only recently been recognized as endonuclease inhibitors. We previously identified luteolin and its glucoside derivate, orientin, as potent endonuclease inhibitors, with their binding illustrated by X-ray crystallography structures. Building on this, we employed a scaffold-hopping approach based on the luteolin structure to design structurally distinct compounds that resemble the flavonoid scaffold. Using an AlphaScreen binding assay, we identified 33 as a submicromolar PA inhibitor with low toxicity. We solved the crystal structure of the PA endonuclease-binding pseudoflavonoid 36, which has similar structure and inhibitory potency to 33. Furthermore, we identified 24, 33, 34 and 36 as inhibitors of influenza polymerase in a minireplicon luciferase reporter assay as well as inhibitors of live H1N1 virus infection in A549 human lung cells.


  • Organizational Affiliation

    Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo n. 2 166 10 Prague 6 Czech Republic milan.kozisek@uochb.cas.cz machara@uochb.cas.cz.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Polymerase acidic protein,Polymerase acidic protein179Influenza A virus (A/California/07/2009(H1N1))Mutation(s): 0 
Gene Names: PA
EC: 3.1
UniProt
Find proteins for C3W5X6 (Influenza A virus)
Explore C3W5X6 
Go to UniProtKB:  C3W5X6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupC3W5X6
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LU2 (Subject of Investigation/LOI)
Query on LU2

Download Ideal Coordinates CCD File 
D [auth A]2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one
C15 H10 O6
IQPNAANSBPBGFQ-UHFFFAOYSA-N
PGE
Query on PGE

Download Ideal Coordinates CCD File 
H [auth A]TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
I [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
DMS
Query on DMS

Download Ideal Coordinates CCD File 
G [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
B [auth A]MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free:  0.264 (Depositor), 0.260 (DCC) 
  • R-Value Work:  0.202 (Depositor), 0.210 (DCC) 
  • R-Value Observed: 0.205 (Depositor) 
Space Group: P 64 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.069α = 90
b = 74.069β = 90
c = 127.715γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PDB_EXTRACTdata extraction
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Ministry of Education (MoE, Czech Republic)Czech RepublicLM2015064
European Regional Development FundCzech RepublicCZ.02.1.01/0.0/0.0/16_019/0000729

Revision History  (Full details and data files)

  • Version 1.0: 2020-09-09
    Type: Initial release
  • Version 1.1: 2020-09-16
    Changes: Database references
  • Version 1.2: 2021-03-17
    Changes: Structure summary
  • Version 1.3: 2024-01-24
    Changes: Data collection, Database references, Refinement description
  • Version 1.4: 2025-07-02
    Changes: Database references, Structure summary