4J7U

Crystal structure of human sepiapterin reductase in complex with sulfathiazole


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.44 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.199 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs.

Haruki, H.Pedersen, M.G.Gorska, K.I.Pojer, F.Johnsson, K.

(2013) Science 340: 987-991

  • DOI: https://doi.org/10.1126/science.1232972
  • Primary Citation of Related Structures:  
    4HWK, 4J7U

  • PubMed Abstract: 

    The introduction of sulfa drugs for the chemotherapy of bacterial infections in 1935 revolutionized medicine. Although their mechanism of action is understood, the molecular bases for most of their side effects remain obscure. Here, we report that sulfamethoxazole and other sulfa drugs interfere with tetrahydrobiopterin biosynthesis through inhibition of sepiapterin reductase. Crystal structures of sepiapterin reductase with bound sulfa drugs reveal how structurally diverse sulfa drugs achieve specific inhibition of the enzyme. The effect of sulfa drugs on tetrahydrobiopterin-dependent neurotransmitter biosynthesis in cell-based assays provides a rationale for some of their central nervous system-related side effects, particularly in high-dose sulfamethoxazole therapy of Pneumocystis pneumonia. Our findings reveal an unexpected aspect of the pharmacology of sulfa drugs and might translate into their improved medical use.


  • Organizational Affiliation

    EPFL, Institute of Chemical Sciences and Engineering, Institute of Bioengineering, National Centre of Competence in Research in Chemical Biology, 1015 Lausanne, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Sepiapterin reductase
A, B, C, D
288Homo sapiensMutation(s): 0 
Gene Names: SPR
EC: 1.1.1.153
UniProt & NIH Common Fund Data Resources
Find proteins for P35270 (Homo sapiens)
Explore P35270 
Go to UniProtKB:  P35270
PHAROS:  P35270
GTEx:  ENSG00000116096 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35270
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP

Download Ideal Coordinates CCD File 
E [auth A],
K [auth B],
P [auth C],
V [auth D]
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
YTZ
Query on YTZ

Download Ideal Coordinates CCD File 
F [auth A],
L [auth B],
Q [auth C],
W [auth D]
4-amino-N-(1,3-thiazol-2-yl)benzenesulfonamide
C9 H9 N3 O2 S2
JNMRHUJNCSQMMB-UHFFFAOYSA-N
PEG
Query on PEG

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

Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
M [auth B]
R [auth C]
S [auth C]
G [auth A],
H [auth A],
M [auth B],
R [auth C],
S [auth C],
X [auth D]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
O [auth B],
U [auth C]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
YTZ Binding MOAD:  4J7U Ki: 14 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.44 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.199 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 147.763α = 90
b = 147.763β = 90
c = 179.503γ = 120
Software Package:
Software NamePurpose
XDSdata scaling
PHASERphasing
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-06-05
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description