6LX4

X-ray structure of human PPARalpha ligand binding domain-fenofibric acid co-crystals obtained by delipidation and co-crystallization


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.13 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

PPAR alpha Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates.

Kamata, S.Oyama, T.Saito, K.Honda, A.Yamamoto, Y.Suda, K.Ishikawa, R.Itoh, T.Watanabe, Y.Shibata, T.Uchida, K.Suematsu, M.Ishii, I.

(2020) iScience 23: 101727-101727

  • DOI: https://doi.org/10.1016/j.isci.2020.101727
  • Primary Citation of Related Structures:  
    6KAX, 6KAY, 6KAZ, 6KB0, 6KB1, 6KB2, 6KB3, 6KB4, 6KB5, 6KB6, 6KB7, 6KB8, 6KB9, 6KBA, 6KYP, 6L36, 6L37, 6L38, 6LX4, 6LX5, 6LX6, 6LX7, 6LX8, 6LX9, 6LXA, 6LXB, 6LXC, 7BPY, 7BPZ, 7BQ0, 7BQ1, 7BQ2, 7BQ3, 7BQ4

  • PubMed Abstract: 

    Most triacylglycerol-lowering fibrates have been developed in the 1960s-1980s before their molecular target, peroxisome proliferator-activated receptor alpha (PPARα), was identified. Twenty-one ligand-bound PPARα structures have been deposited in the Protein Data Bank since 2001; however, binding modes of fibrates and physiological ligands remain unknown. Here we show thirty-four X-ray crystallographic structures of the PPARα ligand-binding domain, which are composed of a "Center" and four "Arm" regions, in complexes with five endogenous fatty acids, six fibrates in clinical use, and six synthetic PPARα agonists. High-resolution structural analyses, in combination with coactivator recruitment and thermostability assays, demonstrate that stearic and palmitic acids are presumably physiological ligands; coordination to Arm III is important for high PPARα potency/selectivity of pemafibrate and GW7647; and agonistic activities of four fibrates are enhanced by the partial agonist GW9662. These results renew our understanding of PPARα ligand recognition and contribute to the molecular design of next-generation PPAR-targeted drugs.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peroxisome proliferator-activated receptor alpha
A, B
273Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q07869 (Homo sapiens)
Explore Q07869 
Go to UniProtKB:  Q07869
PHAROS:  Q07869
GTEx:  ENSG00000186951 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07869
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
F5A BindingDB:  6LX4 Ki: 3.50e+4 (nM) from 1 assay(s)
IC50: min: 1.00e+4, max: 1.06e+5 (nM) from 5 assay(s)
EC50: min: 2646, max: 1.31e+5 (nM) from 13 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.13 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.941α = 90
b = 100.048β = 101.61
c = 62.022γ = 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
Ministry of Education, Culture, Sports, Science and Technology (Japan)Japan16H05107

Revision History  (Full details and data files)

  • Version 1.0: 2020-11-11
    Type: Initial release
  • Version 1.1: 2020-12-02
    Changes: Database references
  • Version 1.2: 2023-11-29
    Changes: Data collection, Database references, Refinement description