3S7S

Crystal structure of human placental aromatase complexed with breast cancer drug exemestane


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.21 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Novel aromatase inhibitors by structure-guided design.

Ghosh, D.Lo, J.Morton, D.Valette, D.Xi, J.Griswold, J.Hubbell, S.Egbuta, C.Jiang, W.An, J.Davies, H.M.

(2012) J Med Chem 55: 8464-8476

  • DOI: https://doi.org/10.1021/jm300930n
  • Primary Citation of Related Structures:  
    3S79, 3S7S, 4GL5, 4GL7

  • PubMed Abstract: 

    Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC(50) values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC(50) values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.


  • Organizational Affiliation

    Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA. ghoshd@upstate.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 19A1503Homo sapiensMutation(s): 0 
Gene Names: CYP19A1ARO1CYARCYP19
EC: 1.14.14.1
UniProt & NIH Common Fund Data Resources
Find proteins for P11511 (Homo sapiens)
Explore P11511 
Go to UniProtKB:  P11511
PHAROS:  P11511
GTEx:  ENSG00000137869 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11511
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
B [auth A]PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
EXM
Query on EXM

Download Ideal Coordinates CCD File 
C [auth A](8alpha,10alpha,13alpha)-6-methylideneandrosta-1,4-diene-3,17-dione
C20 H24 O2
BFYIZQONLCFLEV-DAELLWKTSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
EXM BindingDB:  3S7S Ki: min: 10, max: 26 (nM) from 2 assay(s)
IC50: min: 43, max: 900 (nM) from 5 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.21 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 140.626α = 90
b = 140.626β = 90
c = 119.024γ = 120
Software Package:
Software NamePurpose
ADSCdata collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2012-06-06 
  • Deposition Author(s): Ghosh, D.

Revision History  (Full details and data files)

  • Version 1.0: 2012-06-06
    Type: Initial release
  • Version 1.1: 2012-09-12
    Changes: Database references
  • Version 1.2: 2012-09-19
    Changes: Database references
  • Version 1.3: 2012-10-24
    Changes: Database references
  • Version 1.4: 2017-11-08
    Changes: Refinement description
  • Version 1.5: 2024-02-28
    Changes: Data collection, Database references, Derived calculations, Structure summary