期刊
ACS CHEMICAL BIOLOGY
卷 11, 期 1, 页码 273-283出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.5b00580
关键词
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资金
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
Synthetic full agonists of PPAR gamma 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 PPAR? 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 PPAR gamma to date. Here, we describe the discovery of a partial agonist, SR2067. A co-crystal structure obtained at 2.2 angstrom resolution demonstrates that interactions with the beta-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 (K-D = 513 nM) as compared to that of full agonist rosiglitazone, yet it has a much slower off rate compared to that of rosiglitazone.
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