4OQV

High resolution crystal structure of human dihydroorotate dehydrogenase bound with DSM338 (N-[3,5-difluoro-4-(trifluoromethyl)phenyl]-5-methyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.23 Å
  • R-Value Free: 0.157 
  • R-Value Work: 0.141 
  • R-Value Observed: 0.142 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors.

Deng, X.Kokkonda, S.El Mazouni, F.White, J.Burrows, J.N.Kaminsky, W.Charman, S.A.Matthews, D.Rathod, P.K.Phillips, M.A.

(2014) J Med Chem 57: 5381-5394

  • DOI: https://doi.org/10.1021/jm500481t
  • Primary Citation of Related Structures:  
    4OQV, 4ORI, 4ORM

  • PubMed Abstract: 

    Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.


  • Organizational Affiliation

    Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas , 6001 Forest Park Boulevard, Dallas, Texas 75390-9041, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydroorotate dehydrogenase (quinone), mitochondrial377Homo sapiensMutation(s): 0 
Gene Names: DHODHDihydroorotate Dehydrogenases
EC: 1.3.5.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q02127 (Homo sapiens)
Explore Q02127 
Go to UniProtKB:  Q02127
PHAROS:  Q02127
GTEx:  ENSG00000102967 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ02127
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FMN
Query on FMN

Download Ideal Coordinates CCD File 
B [auth A]FLAVIN MONONUCLEOTIDE
C17 H21 N4 O9 P
FVTCRASFADXXNN-SCRDCRAPSA-N
2V6
Query on 2V6

Download Ideal Coordinates CCD File 
D [auth A]N-[3,5-difluoro-4-(trifluoromethyl)phenyl]-5-methyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
C14 H7 F8 N5
JEEOGRYTTNEULC-UHFFFAOYSA-N
ORO
Query on ORO

Download Ideal Coordinates CCD File 
C [auth A]OROTIC ACID
C5 H4 N2 O4
PXQPEWDEAKTCGB-UHFFFAOYSA-N
SO4
Query on SO4

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I [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACY
Query on ACY

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A]
ACETIC ACID
C2 H4 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
H [auth A],
J [auth A]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2V6 BindingDB:  4OQV IC50: min: 49, max: 2100 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.23 Å
  • R-Value Free: 0.157 
  • R-Value Work: 0.141 
  • R-Value Observed: 0.142 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.936α = 90
b = 90.936β = 90
c = 121.938γ = 120
Software Package:
Software NamePurpose
HKL-3000data collection
PHASESphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-06-04
    Type: Initial release
  • Version 1.1: 2014-07-09
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations