3D90

Crystal structure of the human progesterone receptor ligand-binding domain bound to levonorgestrel


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.26 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.231 
  • R-Value Observed: 0.231 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Met909 plays a key role in the activation of the progesterone receptor and also in the high potency of 13-ethyl progestins

Petit-Topin, I.Turque, N.Fagart, J.Fay, M.Ulmann, A.Gainer, E.Rafestin-Oblin, M.E.

(2009) Mol Pharmacol 75: 1317-1324

  • DOI: https://doi.org/10.1124/mol.108.054312
  • Primary Citation of Related Structures:  
    3D90

  • PubMed Abstract: 

    Many progestins have been developed for use in contraception, menopausal hormone therapy, and treatment of gynecological diseases. They are derived from either progesterone or testosterone, and they act by binding to the progesterone receptor (PR), a hormone-inducible transcription factor belonging to the nuclear receptor superfamily. Unlike mineralocorticoid, glucocorticoid, and androgen receptors, the steroid-receptor contacts that trigger the switch of the ligand-binding domain from an inactive to an active conformation have not yet been identified for the PR. With this aim, we solved the crystal structure of the ligand-binding domain of the human PR complexed with levonorgestrel, a potent testosterone-derived progestin characterized by a 13-ethyl substituent. Via mutagenesis analysis and functional studies, we identified Met909 of the helix 12 as the key residue for PR activation by both testosterone- and progesterone-derived progestins with a 13-methyl or a 13-ethyl substituent. We also showed that Asn719 contributes to PR activation by testosterone-derived progestins only, and that Met759 and Met909 are responsible for the high potency of 19-norprogestins and of 13-ethyl progestins, respectively. Our findings provide a structural guideline for the rational synthesis of potent PR agonist and antagonist ligands that could have therapeutic uses in women's health.


  • Organizational Affiliation

    INSERM U, Centre de Recherche Biomédicale Bichat-Beaujon, Paris, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Progesterone receptor
A, B
258Homo sapiensMutation(s): 0 
Gene Names: PGRNR3C3
UniProt & NIH Common Fund Data Resources
Find proteins for P06401 (Homo sapiens)
Explore P06401 
Go to UniProtKB:  P06401
PHAROS:  P06401
GTEx:  ENSG00000082175 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06401
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NOG
Query on NOG

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
13-BETA-ETHYL-17-ALPHA-ETHYNYL-17-BETA-HYDROXYGON-4-EN-3-ONE
C21 H28 O2
WWYNJERNGUHSAO-XUDSTZEESA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.26 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.231 
  • R-Value Observed: 0.231 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.87α = 90
b = 65.31β = 96.01
c = 70.62γ = 90
Software Package:
Software NamePurpose
CNSrefinement
Xnemodata collection
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-05-26
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description