1ZQ5

Crystal structure of human androgenic 17beta-hydroxysteroid dehydrogenase type 5 in complexed with a potent inhibitor EM1404


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-based inhibitor design for an enzyme that binds different steroids: a potent inhibitor for human type 5 17beta-hydroxysteroid dehydrogenase.

Qiu, W.Zhou, M.Mazumdar, M.Azzi, A.Ghanmi, D.Luu-The, V.Labrie, F.Lin, S.X.

(2007) J Biol Chem 282: 8368-8379

  • DOI: https://doi.org/10.1074/jbc.M606784200
  • Primary Citation of Related Structures:  
    1ZQ5, 2FGB

  • PubMed Abstract: 

    Human type 5 17beta-hydroxysteroid dehydrogenase plays a crucial role in local androgen formation in prostate tissue. Several chemicals were synthesized and tested for their ability to inhibit this enzyme, and a series of estradiol derivatives bearing a lactone on the D-ring were found to inhibit its activity efficiently. The crystal structure of the type 5 enzyme in complex with NADP and such a novel inhibitor, EM1404, was determined to a resolution of 1.30 A. Significantly more hydrogen bonding and hydrophobic interactions were defined between EM1404 and the enzyme than in the substrate ternary complex. The lactone ring of EM1404 accounts for important interactions with the enzyme, whereas the amide group at the opposite end of the inhibitor contributes to the stability of three protein loops involved in the construction of the substrate binding site. EM1404 has a strong competitive inhibition, with a Ki of 6.9+/-1.4 nM, demonstrating 40 times higher affinity than that of the best inhibitor previously reported. This is observed despite the fact that the inhibitor occupies only part of the binding cavity. Attempts to soak the inhibitor into crystals of the binary complex with NADP were unsuccessful, yielding a structure with a polyethylene glycol fragment occupying the substrate binding site. The relative crystal packing is discussed. Combined studies of small molecule inhibitor synthesis, x-ray crystallography, enzyme inhibition, and molecular modeling make it possible to analyze the plasticity of the substrate binding site of the enzyme, which is essential for developing more potent and specific inhibitors for hormone-dependent cancer therapy.


  • Organizational Affiliation

    Canadian Institutes of Health Research Group in Molecular Endocrinology, Laval University Medical Center, Centre Hospitalier de Universités de Québec and Laval University, Quebec G1V 4G2, Canada.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aldo-keto reductase family 1 member C3323Homo sapiensMutation(s): 0 
Gene Names: AKR1C3DDH1KIAA0119PGFS
EC: 1.1.1.62 (PDB Primary Data), 1.3.1.20 (PDB Primary Data), 1.1.1.188 (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 
D [auth A]NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
E04
Query on E04

Download Ideal Coordinates CCD File 
C [auth A]3-CARBOXAMIDO-1,3,5(10)-ESTRATRIEN-17(R)-SPIRO-2'(5',5'-DIMETHYL-6'OXO)TETRAHYDROPYRAN
C25 H33 N O3
YVAJWBACBRSVPR-NDUHRLLKSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
B [auth A]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
E04 BindingDB:  1ZQ5 Ki: 6.9 (nM) from 1 assay(s)
Binding MOAD:  1ZQ5 Ki: 6.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.347α = 90
b = 62.781β = 90
c = 95.974γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
REFMACrefinement
CCP4data 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: 2006-12-12
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description