SR2067 reveals a unique kinetic and structural signature for PPARγ partial agonism

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.

doi:10.1021/acschembio.5b00580

SR2067 reveals a unique kinetic and structural signature for PPARγ partial agonism

Journal Article · Wed Nov 18 00:00:00 EST 2015 · ACS Chemical Biology

DOI:https://doi.org/10.1021/acschembio.5b00580· OSTI ID:1345039

van Marrewijk, Laura M. ^[1]; Polyak, Steven W. ^[2]; Hijnen, Marcel ^[3]; Kuruvilla, Dana ^[4]; Chang, Mi Ra ^[4]; Shin, Youseung ^[4]; Kamenecka, Theodore M. ^[4]; Griffin, Patrick R. ^[4]; Bruning, John B. ^[2]

The Univ. of Adelaide, Adelaide, SA (Australia); Office of Scientific and Technical Information (OSTI)
The Univ. of Adelaide, Adelaide, SA (Australia)
GE Healthcare Life Sciences ANZ, Melbourne, VIC (Australia)
The Scripps Research Inst., Jupiter, FL (United States)

Here, 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. In this paper, 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. Finally, 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.

View Accepted Manuscript (DOE)

Research Organization:: Scripps Research Inst., Jupiter, FL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1345039

Journal Information:: ACS Chemical Biology, Journal Name: ACS Chemical Biology Journal Issue: 1 Vol. 11; ISSN 1554-8929

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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