3UGR

AKR1C3 complex with indomethacin at pH 6.8


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.171 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Crystal structures of three classes of non-steroidal anti-inflammatory drugs in complex with aldo-keto reductase 1C3.

Flanagan, J.U.Yosaatmadja, Y.Teague, R.M.Chai, M.Z.Turnbull, A.P.Squire, C.J.

(2012) PLoS One 7: e43965-e43965

  • DOI: https://doi.org/10.1371/journal.pone.0043965
  • Primary Citation of Related Structures:  
    3R43, 3R58, 3R6I, 3R7M, 3R8G, 3R8H, 3R94, 3UFY, 3UG8, 3UGR

  • PubMed Abstract: 

    Aldo-keto reductase 1C3 (AKR1C3) catalyses the NADPH dependent reduction of carbonyl groups in a number of important steroid and prostanoid molecules. The enzyme is also over-expressed in prostate and breast cancer and its expression is correlated with the aggressiveness of the disease. The steroid products of AKR1C3 catalysis are important in proliferative signalling of hormone-responsive cells, while the prostanoid products promote prostaglandin-dependent proliferative pathways. In these ways, AKR1C3 contributes to tumour development and maintenance, and suggest that inhibition of AKR1C3 activity is an attractive target for the development of new anti-cancer therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) are one well-known class of compounds that inhibits AKR1C3, yet crystal structures have only been determined for this enzyme with flufenamic acid, indomethacin, and closely related analogues bound. While the flufenamic acid and indomethacin structures have been used to design novel inhibitors, they provide only limited coverage of the NSAIDs that inhibit AKR1C3 and that may be used for the development of new AKR1C3 targeted drugs. To understand how other NSAIDs bind to AKR1C3, we have determined ten crystal structures of AKR1C3 complexes that cover three different classes of NSAID, N-phenylanthranilic acids (meclofenamic acid, mefenamic acid), arylpropionic acids (flurbiprofen, ibuprofen, naproxen), and indomethacin analogues (indomethacin, sulindac, zomepirac). The N-phenylanthranilic and arylpropionic acids bind to common sites including the enzyme catalytic centre and a constitutive active site pocket, with the arylpropionic acids probing the constitutive pocket more effectively. By contrast, indomethacin and the indomethacin analogues sulindac and zomepirac, display three distinctly different binding modes that explain their relative inhibition of the AKR1C family members. This new data from ten crystal structures greatly broadens the base of structures available for future structure-guided drug discovery efforts.


  • Organizational Affiliation

    Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.


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 
Gene Names: AKR1C3DDH1HSD17B5KIAA0119PGFS
EC: 1.1.1.213 (PDB Primary Data), 1.1.1.112 (PDB Primary Data), 1.1.1.188 (PDB Primary Data), 1.1.1.63 (PDB Primary Data), 1.1.1.64 (PDB Primary Data), 1.3.1.20 (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
Binding Affinity Annotations 
IDSourceBinding Affinity
IMN BindingDB:  3UGR Ki: min: 270, max: 1.00e+5 (nM) from 5 assay(s)
IC50: min: 100, max: 1.30e+5 (nM) from 14 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.171 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.957α = 90
b = 63.287β = 90
c = 96.394γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
REFMACrefinement
XDSdata reduction
SCALAdata 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: 2012-08-15
    Type: Initial release
  • Version 1.1: 2014-11-05
    Changes: Database references
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description