5L7T

17beta-hydroxysteroid dehydrogenase 14 variant T205 in complex with a non-steroidal inhibitor.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.157 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

First Structure-Activity Relationship of 17 beta-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme.

Braun, F.Bertoletti, N.Moller, G.Adamski, J.Steinmetzer, T.Salah, M.Abdelsamie, A.S.van Koppen, C.J.Heine, A.Klebe, G.Marchais-Oberwinkler, S.

(2016) J Med Chem 59: 10719-10737

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01436
  • Primary Citation of Related Structures:  
    5EN4, 5L7T, 5L7W, 5L7Y

  • PubMed Abstract: 

    17β-HSD14 belongs to the SDR family and oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD + as cofactor. The goal of this study was to identify and optimize 17β-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17β-HSD1 and 17β-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17β-HSD14 inhibition. The most interesting hit was taken as starting point for chemical modification applying a ligand-based approach. The designed compounds were synthesized and tested for 17β-HSD14 inhibitory activity. The two best inhibitors identified in this study have a very high affinity to the enzyme with a K i equal to 7 nM. The strong affinity of these inhibitors to the enzyme active site could be explained by crystallographic structure analysis, which highlighted the role of an extended H-bonding network in the stabilization process. The selectivity of the most potent compounds with respect to 17β-HSD1 and 17β-HSD2 is also addressed.


  • Organizational Affiliation

    Institute for Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
17-beta-hydroxysteroid dehydrogenase 14274Homo sapiensMutation(s): 0 
Gene Names: HSD17B14DHRS10SDR3SDR47C1UNQ502/PRO474
EC: 1.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9BPX1 (Homo sapiens)
Explore Q9BPX1 
Go to UniProtKB:  Q9BPX1
PHAROS:  Q9BPX1
GTEx:  ENSG00000087076 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9BPX1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAD
Query on NAD

Download Ideal Coordinates CCD File 
B [auth A]NICOTINAMIDE-ADENINE-DINUCLEOTIDE
C21 H27 N7 O14 P2
BAWFJGJZGIEFAR-NNYOXOHSSA-N
6QJ
Query on 6QJ

Download Ideal Coordinates CCD File 
D [auth A](4-fluoranyl-3-oxidanyl-phenyl)-[6-(3-methyl-4-oxidanyl-phenyl)pyridin-2-yl]methanone
C19 H14 F N O3
QDDLZOOWBSJEFI-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
C [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6QJ Binding MOAD:  5L7T Ki: 26 (nM) from 1 assay(s)
BindingDB:  5L7T Ki: 26 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.157 
  • Space Group: I 4 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.243α = 90
b = 91.243β = 90
c = 131.398γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Research FoundationGermanyKL-1204/15-1
German Research FoundationGermanyMA-5287/1-1

Revision History  (Full details and data files)

  • Version 1.0: 2016-12-21
    Type: Initial release
  • Version 1.1: 2017-09-06
    Changes: Author supporting evidence, Data collection
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Refinement description