5K6A | pdb_00005k6a

Trypanosoma brucei Pteridine reductase 1 (PTR1) in complex with compound 1

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 
    0.220 (Depositor), 0.220 (DCC) 
  • R-Value Work: 
    0.180 (Depositor), 0.180 (DCC) 
  • R-Value Observed: 
    0.182 (Depositor) 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history. 


Literature

Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity.

Di Pisa, F., Landi, G., Dello Iacono, L., Pozzi, C., Borsari, C., Ferrari, S., Santucci, M., Santarem, N., Cordeiro-da-Silva, A., Moraes, C.B., Alcantara, L.M., Fontana, V., Freitas-Junior, L.H., Gul, S., Kuzikov, M., Behrens, B., Pohner, I., Wade, R.C., Costi, M.P., Mangani, S.

(2017) Molecules 22

  • DOI: https://doi.org/10.3390/molecules22030426
  • Primary Citation of Related Structures:  
    5K6A, 5L42, 5L4N

  • PubMed Abstract: 

    Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues ( 1 - 3 ) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes ( Trypanosoma brucei PTR1- Tb PTR1 and Leishmania major-Lm PTR1) and parasites ( Trypanosoma brucei and Leishmania infantum ). A crystal structure of Tb PTR1 in complex with compound 1 and the first crystal structures of Lm PTR1-flavanone complexes (compounds 1 and 3 ) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.

    • Organizational Affiliation: 
    • Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy. dipisa2@unisi.it.

Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Pteridine reductase
A, B, D
288Trypanosoma brucei bruceiMutation(s): 0 
Gene Names: PTR1
UniProt
Find proteins for O76290 (Trypanosoma brucei brucei)
Explore O76290 
Go to UniProtKB:  O76290
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO76290
Sequence Annotations
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  • Reference Sequence
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(by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Pteridine reductase288Trypanosoma brucei bruceiMutation(s): 0 
Gene Names: PTR1
UniProt
Find proteins for O76290 (Trypanosoma brucei brucei)
Explore O76290 
Go to UniProtKB:  O76290
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO76290
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP
Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
J [auth C],
M [auth D]		NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
6QT
Query on 6QT
Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
K [auth C],
N [auth D]		(2~{R})-2-(3-hydroxyphenyl)-6-oxidanyl-2,3-dihydrochromen-4-one
C15 H12 O4
FTDCCBIDVVGONG-OAHLLOKOSA-N
ACT
Query on ACT
Download Ideal Coordinates CCD File 
G [auth A],
L [auth C]		ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
CSX
Query on CSX
A, B, D
L-PEPTIDE LINKINGC3 H7 N O3 SCYS
OCS
Query on OCS
C
L-PEPTIDE LINKINGC3 H7 N O5 SCYS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free:  0.220 (Depositor), 0.220 (DCC) 
  • R-Value Work:  0.180 (Depositor), 0.180 (DCC) 
  • R-Value Observed: 0.182 (Depositor) 
Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.72α = 90
b = 89.894β = 115.75
c = 82.684γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
iMOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-03-22
    Type: Initial release
  • Version 1.1: 2024-01-10
    Changes: Data collection, Database references, Refinement description