Open AccessSR2067 Reveals a Unique Kinetic and Structural Signature for PPARγ Partial Agonism
Author(s) -
Laura M. van Marrewijk,
Steven W. Polyak,
Marcel Hijnen,
Dana S. Kuruvilla,
Mi Ra Chang,
Youseung Shin,
Theodore M. Kamenecka,
Patrick R. Griffin,
John B. Bruning
Publication year - 2015
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.5b00580
Subject(s) - rosiglitazone , partial agonist , agonism , agonist , surface plasmon resonance , chemistry , receptor , glucose homeostasis , pharmacology , medicine , biophysics , stereochemistry , insulin , biology , biochemistry , materials science , insulin resistance , nanotechnology , politics , political science , nanoparticle , law
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.