8BBS

Structure of AKR1C3 in complex with a bile acid fused tetrazole inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.177 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.155 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

X-ray structure of human aldo-keto reductase 1C3 in complex with a bile acid fused tetrazole inhibitor: experimental validation, molecular docking and structural analysis.

Marinovic, M.A.Bekic, S.S.Kugler, M.Brynda, J.Skerlova, J.Skoric, D.D.Rezacova, P.Petri, E.T.Celic, A.S.

(2023) RSC Med Chem 14: 341-355

  • DOI: https://doi.org/10.1039/d2md00387b
  • Primary Citation of Related Structures:  
    8BBS

  • PubMed Abstract: 

    Aldo-keto reductase 1C3 (AKR1C3) catalyzes the reduction of androstenedione to testosterone and reduces the effectiveness of chemotherapeutics. AKR1C3 is a target for treatment of breast and prostate cancer and AKR1C3 inhibition could be an effective adjuvant therapy in the context of leukemia and other cancers. In the present study, steroidal bile acid fused tetrazoles were screened for their ability to inhibit AKR1C3. Four C24 bile acids with C-ring fused tetrazoles were moderate to strong AKR1C3 inhibitors (37-88% inhibition), while B-ring fused tetrazoles had no effect on AKR1C3 activity. Based on a fluorescence assay in yeast cells, these four compounds displayed no affinity for estrogen receptor-α, or the androgen receptor, suggesting a lack of estrogenic or androgenic effects. A top inhibitor showed specificity for AKR1C3 over AKR1C2, and inhibited AKR1C3 with an IC 50 of ∼7 μM. The structure of AKR1C3·NADP + in complex with this C-ring fused bile acid tetrazole was determined by X-ray crystallography at 1.4 Å resolution, revealing that the C24 carboxylate is anchored to the catalytic oxyanion site (H117, Y55); meanwhile the tetrazole interacts with a tryptophan (W227) important for steroid recognition. Molecular docking predicts that all four top AKR1C3 inhibitors bind with nearly identical geometry, suggesting that C-ring bile acid fused tetrazoles represent a new class of AKR1C3 inhibitors.


  • Organizational Affiliation

    Faculty of Sciences, Department of Biology and Ecology, University of Novi Sad Trg Dositeja Obradovića 2 21000 Novi Sad Serbia [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aldo-keto reductase family 1 member C3A [auth B],
B [auth A]
326Homo sapiensMutation(s): 0 
Gene Names: AKR1C3DDH1HSD17B5KIAA0119PGFS
EC: 1.1.1 (PDB Primary Data), 1.1.1.210 (PDB Primary Data), 1.1.1.53 (PDB Primary Data), 1.1.1.62 (PDB Primary Data), 1.1.1.357 (PDB Primary Data), 1.1.1.188 (PDB Primary Data), 1.1.1.239 (PDB Primary Data), 1.1.1.64 (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 (Subject of Investigation/LOI)
Query on NAP

Download Ideal Coordinates CCD File 
C [auth B],
I [auth A]
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
QBO (Subject of Investigation/LOI)
Query on QBO

Download Ideal Coordinates CCD File 
D [auth B],
J [auth A]
(4~{R})-4-[(1~{R},2~{S},5~{R},6~{R},13~{S},14~{S},17~{R},19~{R})-6,14-dimethyl-17-oxidanyl-7,8,9,10-tetrazapentacyclo[11.8.0.0^{2,6}.0^{7,11}.0^{14,19}]henicosa-8,10-dien-5-yl]pentanoic acid
C24 H38 N4 O3
MIQKAEOABWRKCI-VPUMZWJWSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
E [auth B]
F [auth B]
G [auth B]
H [auth B]
K [auth A]
E [auth B],
F [auth B],
G [auth B],
H [auth B],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
QBO BindingDB:  8BBS IC50: 7000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.177 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.155 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.462α = 77.26
b = 51.413β = 86.74
c = 77.879γ = 77.63
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Other governmentSerbia451-03-9/2021-14/ 200125
Other governmentSerbia142-451-3177/2020-03
Other governmentEuropean UnionLX22NPO5102

Revision History  (Full details and data files)

  • Version 1.0: 2023-03-08
    Type: Initial release
  • Version 2.0: 2023-05-24
    Changes: Non-polymer description
  • Version 2.1: 2024-02-07
    Changes: Data collection, Refinement description