6I6F

SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 1

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors.

Alen, J., Schade, M., Wagener, M., Christian, F., Nordhoff, S., Merla, B., Dunkern, T.R., Bahrenberg, G., Ratcliffe, P.

(2019) J Med Chem 62: 6391-6397

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00218
  • Primary Citation of Related Structures:  
    6I6C, 6I6F, 6I6P, 6I6T, 6I6V, 6I79

  • PubMed Abstract: 

    Genome-wide-association studies in chronic low back pain patients identified sepiapterin reductase as a high interest target for developing new analgesics. Here we used 19 F NMR fragment screening for the discovery of novel, ligand-efficient SPR inhibitors. We report the crystal structures of six chemically diverse inhibitors complexed with SPR, identifying relevant interactions and binding modes in the sepiapterin pocket. Exploration of our initial fragment screening hit led to double-digit nanomolar inhibitors of SPR with excellent ligand efficiency.

    • Organizational Affiliation: 

    Grünenthal GmbH , Zieglerstraße 6 , 52078 Aachen , Germany.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Sepiapterin reductase
A, B
276Homo 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
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP
Download Ideal Coordinates CCD File 
C [auth A],
N [auth B]		NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
H4E
Query on H4E
Download Ideal Coordinates CCD File 
D [auth A]ethyl 4-azanyl-3-bromanyl-benzoate
C9 H10 Br N O2
NOGUJGZZMMKQOZ-UHFFFAOYSA-N
EDO
Query on EDO
Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
O [auth B],
P [auth B],
Q [auth B],
R [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.154α = 90
b = 77.194β = 90
c = 114.854γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing

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: 2019-07-10
    Type: Initial release
  • Version 1.1: 2019-07-24
    Changes: Data collection, Database references
  • Version 1.2: 2024-05-15
    Changes: Advisory, Data collection, Database references