SR2067 reveals a unique kinetic and structural signature for PPARγ partial agonism
| Autor: | John B. Bruning, Mi Ra Chang, Dana S. Kuruvilla, Patrick R. Griffin, Laura M. van Marrewijk, Steven W. Polyak, Youseung Shin, Marcel Hijnen, Theodore M. Kamenecka |
|---|---|
| Přispěvatelé: | Van Marrewijk, Laura M, Polyak, Steven W, Hijnen, Marcel, Kuruvilla, Dana, Chang, Mi Ra, Shin, Youseung, Kamenecka, Theodore M, Griffin, Patrick R, Bruning, John B |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Agonist medicine.medical_specialty Indoles medicine.drug_class medicine.medical_treatment Peroxisome proliferator-activated receptor Crystallography X-Ray Biochemistry Partial agonist Article 03 medical and health sciences Internal medicine medicine Humans Glucose homeostasis Binding site Receptor synthetic full agonists of PPARγ treatment of diabetes chemistry.chemical_classification Sulfonamides Binding Sites Insulin PPARs (peroxisome proliferator-activated receptors) General Medicine PPAR gamma Kinetics 030104 developmental biology Endocrinology chemistry Biophysics Molecular Medicine Rosiglitazone medicine.drug |
| Popis: | Synthetic full agonists of PPARγ have been prescribed for the treatment of diabetes due to their ability to regulate glucose homeostasis and insulin sensitization. While the use of full agonists of PPARγ has been hampered due to severe side effects, partial agonists have shown promise due to their decreased incidence of such side effects in preclinical models. No kinetic information has been forthcoming in regard to the mechanism of full versus partial agonism of PPARγ to date. Here, we describe the discovery of a partial agonist, SR2067. A co-crystal structure obtained at 2.2 Å resolution demonstrates that interactions with the β-sheet are driven exclusively via hydrophobic interactions mediated through a naphthalene group, an observation that is unique from other partial agonists. Surface plasmon resonance revealed that SR2067 binds to the receptor with higher affinity (KD= 513 nM) as compared to that of full agonist rosiglitazone, yet it has a much slower off rate compared to that of rosiglitazone. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|