3B1M

Crystal structure of the PPARgamma-LBD complexed with a cercosporamide derivative modulator Cerco-A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.217 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Pharmacology and in Vitro Profiling of a Novel Peroxisome Proliferator-Activated Receptor gamma Ligand, Cerco-A

Wakabayashi, K.Hayashi, S.Matsui, Y.Matsumoto, T.Furukawa, A.Kuroha, M.Tanaka, N.Inaba, T.Kanda, S.Tanaka, J.Okuyama, R.Wakimoto, S.Ogata, T.Araki, K.Ohsumi, J.

(2011) Biol Pharm Bull 34: 1094-1104

  • DOI: https://doi.org/10.1248/bpb.34.1094
  • Primary Citation of Related Structures:  
    3B1M

  • PubMed Abstract: 

    Peroxisome proliferator-activated receptor γ (PPARγ; NR1C3) is known as a key regulator of adipocytogenesis and the molecular target of thiazolidinediones (TZDs), also known as antidiabetic agents. Despite the clinical benefits of TZDs, their use is often associated with adverse effects including peripheral edema, congestive heart failure, and weight gain. Here we report the identification and characterization of a non-thiazolidinedione PPARγ partial agonist, Cerco-A, which is a derivative of the natural product, (-)-cercosporamide. Cerco-A was found to be a binder of the PPARγ ligand-binding domain in a ligand competitive binding assay and showed a unique cofactor recruitment profile compared to rosiglitazone. A crystal structure analysis revealed that Cerco-A binds to PPARγ without direct hydrogen bonding to helix12. In PPARγ transcriptional activation assay and an adipocyte differentiation assay, Cerco-A was a potent partial agonist of PPARγ. After a 14-day oral administration, once per day of Cerco-A in Zucker diabetic fatty (ZDF) rats, an apparent decrease of plasma glucose and triglyceride was observed, as with pioglitazone. To evaluate drug safety, Cerco-A was administered for 13 days orally in non-diabetic Zucker fatty (ZF) rats. Each of the hemodilution parameters (hematocrit, red blood cells number, and hemoglobin), which are considered as undesirable effects of TZDs, was improved significantly compared to pioglitazone. While Cerco-A showed body weight gain, as with pioglitazone, Cerco-A had significantly lower effects on heart and white adipose tissues weight gain. The results suggest that Cerco-A offers beneficial effects on glycemic control with attenuated undesirable side effects.


  • Organizational Affiliation

    Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305–8577, Japan. wakabayashi.kenji.vy@rda.daiichisankyo.co.jp


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peroxisome proliferator-activated receptor gamma283Homo sapiensMutation(s): 0 
Gene Names: PPARGNR1C3
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
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha19Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UBK2 (Homo sapiens)
Explore Q9UBK2 
Go to UniProtKB:  Q9UBK2
PHAROS:  Q9UBK2
GTEx:  ENSG00000109819 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UBK2
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KRC
Query on KRC

Download Ideal Coordinates CCD File 
C [auth A](9aS)-8-acetyl-N-[(2-ethylnaphthalen-1-yl)methyl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-4-carboxamide
C30 H27 N O7
CCHJJXMWNNECOU-SSEXGKCCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
KRC PDBBind:  3B1M Ki: 3.3 (nM) from 1 assay(s)
Binding MOAD:  3B1M Ki: 3.3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.217 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 38.946α = 90
b = 54.622β = 92.21
c = 66.782γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-08-24
    Type: Initial release
  • Version 1.1: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description