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

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.
Authors:
 [1] ;  [1] ;  [2] ;  [3] ;  [3] ;  [3] ;  [3] ;  [3] ;  [1]
  1. The Univ. of Adelaide, Adelaide, SA (Australia)
  2. GE Healthcare Life Sciences ANZ, Melbourne, VIC (Australia)
  3. The Scripps Research Inst., Jupiter, FL (United States)
Publication Date:
Grant/Contract Number:
AC02-76SF00515
Type:
Accepted Manuscript
Journal Name:
ACS Chemical Biology
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 1554-8929
Publisher:
American Chemical Society (ACS)
Research Org:
Scripps Research Inst., Jupiter, FL (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
OSTI Identifier:
1345039

van Marrewijk, Laura M., Polyak, Steven W., Hijnen, Marcel, Kuruvilla, Dana, Chang, Mi Ra, Shin, Youseung, Kamenecka, Theodore M., Griffin, Patrick R., and Bruning, John B.. SR2067 reveals a unique kinetic and structural signature for PPARγ partial agonism. United States: N. p., Web. doi:10.1021/acschembio.5b00580.
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.. SR2067 reveals a unique kinetic and structural signature for PPARγ partial agonism. United States. doi:10.1021/acschembio.5b00580.
van Marrewijk, Laura M., Polyak, Steven W., Hijnen, Marcel, Kuruvilla, Dana, Chang, Mi Ra, Shin, Youseung, Kamenecka, Theodore M., Griffin, Patrick R., and Bruning, John B.. 2015. "SR2067 reveals a unique kinetic and structural signature for PPARγ partial agonism". United States. doi:10.1021/acschembio.5b00580. https://www.osti.gov/servlets/purl/1345039.
@article{osti_1345039,
title = {SR2067 reveals a unique kinetic and structural signature for PPARγ partial agonism},
author = {van Marrewijk, Laura M. and Polyak, Steven W. and Hijnen, Marcel and Kuruvilla, Dana and Chang, Mi Ra and Shin, Youseung and Kamenecka, Theodore M. and Griffin, Patrick R. and Bruning, John B.},
abstractNote = {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 (KD = 513 nM) as compared to that of full agonist rosiglitazone, yet it has a much slower off rate compared to that of rosiglitazone.},
doi = {10.1021/acschembio.5b00580},
journal = {ACS Chemical Biology},
number = 1,
volume = 11,
place = {United States},
year = {2015},
month = {11}
}