1S2C

Crystal structures of prostaglandin D2 11-ketoreductase in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 

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This is version 1.3 of the entry. See complete history


Literature

Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin.

Lovering, A.L.Ride, J.P.Bunce, C.M.Desmond, J.C.Cummings, S.M.White, S.A.

(2004) Cancer Res 64: 1802-1810

  • DOI: https://doi.org/10.1158/0008-5472.can-03-2847
  • Primary Citation of Related Structures:  
    1S1P, 1S1R, 1S2A, 1S2C

  • PubMed Abstract: 

    It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin loop, at the opposite end of the central beta-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.


  • Organizational Affiliation

    The School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aldo-keto reductase family 1 member C3331Homo sapiensMutation(s): 0 
EC: 1.1.1.213 (PDB Primary Data), 1.3.1.20 (PDB Primary Data), 1.1.1.62 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P42330 (Homo sapiens)
Explore P42330 
Go to UniProtKB:  P42330
PHAROS:  P42330
GTEx:  ENSG00000196139 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP42330
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 
B [auth A]NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
FLF
Query on FLF

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID
C14 H10 F3 N O2
LPEPZBJOKDYZAD-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
E [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FLF BindingDB:  1S2C Ki: min: 140, max: 3100 (nM) from 2 assay(s)
IC50: min: 50, max: 8630 (nM) from 12 assay(s)
Binding MOAD:  1S2C Ki: 140 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.798α = 90
b = 63β = 90
c = 96.289γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
CCP4data scaling
CNSphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-03-23
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-10-25
    Changes: Data collection, Database references, Derived calculations, Refinement description