3QWH

Crystal structure of the 17beta-hydroxysteroid dehydrogenase from Cochliobolus lunatus in complex with NADPH and kaempferol


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.62 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.172 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural basis for inhibition of 17 beta-hydroxysteroid dehydrogenases by phytoestrogens: The case of fungal 17 beta-HSDcl.

Cassetta, A.Stojan, J.Krastanova, I.Kristan, K.Brunskole Svegelj, M.Lamba, D.Rizner, T.L.

(2017) J Steroid Biochem Mol Biol 171: 80-93

  • DOI: https://doi.org/10.1016/j.jsbmb.2017.02.020
  • Primary Citation of Related Structures:  
    3QWH, 4FJ0, 4FJ1, 4FJ2

  • PubMed Abstract: 

    Phytoestrogens are plant-derived compounds that functionally and structurally mimic mammalian estrogens. Phytoestrogens have broad inhibitory activities toward several steroidogenic enzymes, such as the 17β-hydroxysteroid dehydrogenases (17β-HSDs), which modulate the biological potency of androgens and estrogens in mammals. However, to date, no crystallographic data are available to explain phytoestrogens binding to mammalian 17β-HSDs. NADP(H)-dependent 17β-HSD from the filamentous fungus Cochliobolus lunatus (17β-HSDcl) has been the subject of extensive biochemical, kinetic and quantitative structure-activity relationship studies that have shown that the flavonols are the most potent inhibitors. In the present study, we investigated the structure-activity relationships of the ternary complexes between the holo form of 17β-HSDcl and the flavonols kaempferol and 3,7-dihydroxyflavone, in comparison with the isoflavones genistein and biochanin A. Crystallographic data are accompanied by kinetic analysis of the inhibition mechanisms for six flavonols (3-hydroxyflavone, 3,7-dihydroxyflavone, kaempferol, quercetin, fisetin, myricetin), one flavanone (naringenin), one flavone (luteolin), and two isoflavones (genistein, biochanin A). The kinetics analysis shows that the degree of hydroxylation of ring B significantly influences the overall inhibitory efficacy of the flavonols. A distinct binding mode defines the interactions between 17β-HSDcl and the flavones and isoflavones. Moreover, the complex with biochanin A reveals an unusual binding mode that appears to account for its greater inhibition of 17β-HSDcl with respect to genistein. Overall, these data provide a blueprint for identification of the distinct molecular determinants that underpin 17β-HSD inhibition by phytoestrogens.


  • Organizational Affiliation

    Istituto di Cristallografia, UOS Trieste, Consiglio Nazionale delle Ricerche, S. S. 14-Km 163.5, I-34149, Trieste, Italy. Electronic address: [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
17beta-hydroxysteroid dehydrogenase
A, B, C, D
270Curvularia lunataMutation(s): 0 
Gene Names: 17HSDcl
EC: 1.1.1.62
UniProt
Find proteins for O93874 (Cochliobolus lunatus)
Explore O93874 
Go to UniProtKB:  O93874
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO93874
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 
E [auth A],
G [auth B],
J [auth C],
K [auth D]
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
KMP
Query on KMP

Download Ideal Coordinates CCD File 
F [auth A],
H [auth B],
L [auth D]
3,5,7-TRIHYDROXY-2-(4-HYDROXYPHENYL)-4H-CHROMEN-4-ONE
C15 H10 O6
IYRMWMYZSQPJKC-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
I [auth B]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.62 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.172 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.95α = 90
b = 116.64β = 102.54
c = 70.24γ = 90
Software Package:
Software NamePurpose
MAR345data collection
MOLREPphasing
REFMACrefinement
MOSFLMdata 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: 2012-03-21
    Type: Initial release
  • Version 1.1: 2017-07-19
    Changes: Database references
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description