7WGQ

X-ray structure of human PPAR gamma ligand binding domain-pemafibrate co-crystals obtained by co-crystallization


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.43 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Functional and Structural Insights into Human PPAR alpha / delta / gamma Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate.

Honda, A.Kamata, S.Akahane, M.Machida, Y.Uchii, K.Shiiyama, Y.Habu, Y.Miyawaki, S.Kaneko, C.Oyama, T.Ishii, I.

(2022) Int J Mol Sci 23

  • DOI: https://doi.org/10.3390/ijms23094726
  • Primary Citation of Related Structures:  
    7WGL, 7WGN, 7WGO, 7WGP, 7WGQ

  • PubMed Abstract: 

    Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays-a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ-bezafibrate, PPARγ-fenofibric acid, and PPARδ/γ-pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.


  • Organizational Affiliation

    Department of Health Chemistry, Showa Pharmaceutical University, Machida 194-8543, Tokyo, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Isoform 1 of Peroxisome proliferator-activated receptor gamma279Homo sapiensMutation(s): 0 
Gene Names: PPARG
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
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
15-meric peptide from Nuclear receptor coactivator 115Homo sapiensMutation(s): 0 
EC: 2.3.1.48
UniProt & NIH Common Fund Data Resources
Find proteins for Q15788 (Homo sapiens)
Explore Q15788 
Go to UniProtKB:  Q15788
PHAROS:  Q15788
GTEx:  ENSG00000084676 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15788
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
P7F (Subject of Investigation/LOI)
Query on P7F

Download Ideal Coordinates CCD File 
C [auth A](2~{R})-2-[3-[[1,3-benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butanoic acid
C28 H30 N2 O6
ZHKNLJLMDFQVHJ-RUZDIDTESA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
P7F BindingDB:  7WGQ EC50: min: 1100, max: 1700 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.43 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.422α = 90
b = 63.32β = 90
c = 123.517γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Japan Society for the Promotion of Science (JSPS)Japan19K16359
Japan Agency for Medical Research and Development (AMED)JapanJP19am0101071

Revision History  (Full details and data files)

  • Version 1.0: 2022-05-25
    Type: Initial release
  • Version 1.1: 2023-11-29
    Changes: Data collection, Refinement description