5JKV

HUMAN PLACENTAL AROMATASE CYTOCHROME P450 (CYP19A1) AT 2.75 ANGSTROM WITH BOUND POLYETHYLENE GLYCOL

  • Classification: OXIDOREDUCTASE
  • Organism(s): Homo sapiens
  • Mutation(s): No 

  • Deposited: 2016-04-26 Released: 2017-04-26 
  • Deposition Author(s): Ghosh, D., Lo, J., Egbuta, C.
  • Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.215 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Testosterone complex and non-steroidal ligands of human aromatase.

Ghosh, D.Egbuta, C.Lo, J.

(2018) J Steroid Biochem Mol Biol 

  • DOI: https://doi.org/10.1016/j.jsbmb.2018.02.009
  • Primary Citation of Related Structures:  
    5JKV, 5JKW, 5JL6, 5JL7, 5JL9

  • PubMed Abstract: 

    Cytochrome P450 aromatase (AROM) catalyzes the biosynthesis of estrogen from androgen. Previously crystal structures of human AROM in complex with the substrate androstenedione, and inhibitors exemestane, as well as the newly designed steroidal compounds, have been reported. Here we report the first crystal structure of testosterone complex of human placental AROM. Testosterone binds at the androgen-specific heme distal pocket. The polar and hydrophobic interactions with the surrounding residues resemble the interactions observed for other ligands. The heme proximal region comprises the intermolecular interface in AROM, and also the putative interaction surface of its redox partner cytochrome P450 reductase. Unreported previously, the proximal region is characterized by a large surface cavity, unlike most known P450's. Using five best X-ray data sets from androstenedione and testosterone complexes of AROM, we now unequivocally show the presence of an unexplained ligand electron density inside the proximal cavity. The density is interpreted as ordered five ethylene glycol units of polyethylene glycols used as a solvent for steroids and also in crystallization. Interestingly, polyethylene glycol exhibits weak inhibition of AROM enzyme activity in a time dependent manner. Besides its critical role in the redox partner coupling and electron transfer process, the proximal cavity possibly serves as the interaction site for other molecules that may have regulatory effects on AROM activity. In addition, the new data also reveal a previously unidentified water channel linking the active site to the lipid interface. The channel could be the predicted passage for water molecules involved in catalysis.


  • Organizational Affiliation

    Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY 13210 United States. Electronic address: ghoshd@upstate.edu.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aromatase503Homo sapiensMutation(s): 0 
EC: 1.14.14.14
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 4 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
ASD
Query on ASD

Download Ideal Coordinates CCD File 
C [auth A]4-ANDROSTENE-3-17-DIONE
C19 H26 O2
AEMFNILZOJDQLW-QAGGRKNESA-N
1PE
Query on 1PE

Download Ideal Coordinates CCD File 
D [auth A]PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A],
H [auth A]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Binding Affinity Annotations 
IDSourceBinding Affinity
ASD BindingDB:  5JKV Ki: 20 (nM) from 1 assay(s)
IC50: 300 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.215 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 140.218α = 90
b = 140.218β = 90
c = 119.271γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM086893

Revision History  (Full details and data files)

  • Version 1.0: 2017-04-26
    Type: Initial release
  • Version 1.1: 2017-09-27
    Changes: Author supporting evidence
  • Version 1.2: 2018-05-30
    Changes: Data collection, Database references
  • Version 1.3: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references