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Structural dataset for the PPARγ V290M mutant
Ana C Puhl1, Paul Webb2, Igor Polikarpov1
1Instituto de Física de São Carlos, Universidade de São Paulo, Av. Trabalhador Saocarlense 400, São Carlos, SP 13560-970, Brazil.
Abstract:
Loss-of-function mutation V290M in the ligand-binding domain of the peroxisome proliferator activated receptor γ (PPARγ) is associated with a ligand resistance syndrome (PLRS), characterized by partial lipodystrophy and severe insulin resistance. In this data article we discuss an X-ray diffraction dataset that yielded the structure of PPARγ LBD V290M mutant refined at 2.3 Å resolution, that allowed building of 3D model of the receptor mutant with high confidence and revealed continuous well-defined electron density for the partial agonist diclofenac bound to hydrophobic pocket of the PPARγ. These structural data provide significant insights into molecular basis of PLRS caused by V290M mutation and are correlated with the receptor disability of rosiglitazone binding and increased affinity for corepressors. Furthermore, our structural evidence helps to explain clinical observations which point out to a failure to restore receptor function by the treatment with a full agonist of PPARγ, rosiglitazone.
Insights
A V290M mutation in peroxisome proliferator activated receptor gamma (PPARγ) causes ligand resistance syndrome. Structural data reveal how this mutation affects drug binding and receptor function, explaining clinical observations.
Area of Science:
- Biochemistry
- Structural Biology
- Genetics
Background:
- Loss-of-function mutation V290M in peroxisome proliferator activated receptor gamma (PPARγ) is linked to ligand resistance syndrome (PLRS).
- PLRS presents with partial lipodystrophy and severe insulin resistance.
Purpose of the Study:
- To present the X-ray diffraction dataset and 3D structural model of the PPARγ LBD V290M mutant.
- To elucidate the molecular basis of PLRS associated with the V290M mutation.
Main Methods:
- X-ray diffraction data collection and structure refinement at 2.3 Å resolution.
- 3D model building of the PPARγ V290M mutant.
Main Results:
- A high-confidence 3D model of the PPARγ V290M mutant was generated.
- Continuous electron density revealed diclofenac bound to the PPARγ hydrophobic pocket.
- Structural data correlate V290M mutation with impaired rosiglitazone binding and increased corepressor affinity.
Conclusions:
- The structural data provide molecular insights into the pathogenesis of PLRS caused by the V290M mutation.
- The findings explain the clinical observation of treatment failure with full PPARγ agonists like rosiglitazone.
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