3ADW

Human PPARgamma ligand-binding domain in complex with 5-methoxy-indole acetate and 15-oxo-eicosatetraenoic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.230 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

The nuclear receptor PPARgamma individually responds to serotonin- and fatty acid-metabolites

Waku, T.Shiraki, T.Oyama, T.Maebara, K.Nakamori, R.Morikawa, K.

(2010) EMBO J 29: 3395-3407

  • DOI: https://doi.org/10.1038/emboj.2010.197
  • Primary Citation of Related Structures:  
    2ZK6, 3ADS, 3ADT, 3ADU, 3ADV, 3ADW, 3ADX

  • PubMed Abstract: 

    The nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ), recognizes various synthetic and endogenous ligands by the ligand-binding domain. Fatty-acid metabolites reportedly activate PPARγ through conformational changes of the Ω loop. Here, we report that serotonin metabolites act as endogenous agonists for PPARγ to regulate macrophage function and adipogenesis by directly binding to helix H12. A cyclooxygenase inhibitor, indomethacin, is a mimetic agonist of these metabolites. Crystallographic analyses revealed that an indole acetate functions as a common moiety for the recognition by the sub-pocket near helix H12. Intriguingly, a serotonin metabolite and a fatty-acid metabolite each bind to distinct sub-pockets, and the PPARγ antagonist, T0070907, blocked the fatty-acid agonism, but not that of the serotonin metabolites. Mutational analyses on receptor-mediated transcription and coactivator binding revealed that each metabolite individually uses coregulator and/or heterodimer interfaces in a ligand-type-specific manner. Furthermore, the inhibition of the serotonin metabolism reduced the expression of the endogenous PPARγ-target gene. Collectively, these results suggest a novel agonism, in which PPARγ functions as a multiple sensor in response to distinct metabolites.


  • Organizational Affiliation

    The Takara Bio Endowed Division, Department of Biomolecular Recognition, Institute for Protein Research, Osaka University, Open Laboratories of Advanced Bioscience and Biotechnology, Furuedai, Suita, Osaka, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peroxisome proliferator-activated receptor gamma
A, B
287Homo sapiensMutation(s): 0 
Gene Names: PPARgamma
UniProt & NIH Common Fund Data Resources
Find proteins for P37231 (Homo sapiens)
Explore P37231 
Go to UniProtKB:  P37231
PHAROS:  P37231
GTEx:  ENSG00000132170 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP37231
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
OCR
Query on OCR

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B]
(5E,8E,11Z,13E)-15-oxoicosa-5,8,11,13-tetraenoic acid
C20 H30 O3
YGJTUEISKATQSM-KIFLIQHDSA-N
MYI
Query on MYI

Download Ideal Coordinates CCD File 
C [auth A](5-methoxy-1H-indol-3-yl)acetic acid
C11 H11 N O3
COCNDHOPIHDTHK-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
MYI Binding MOAD:  3ADW Kd: 7.28e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.230 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.034α = 90
b = 61.181β = 102.84
c = 118.475γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-12-22
    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