title: SR2067 Reveals a Unique Kinetic and Structural Signature for PPARγ Partial Agonism.
abstract: 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.
authors.affiliation: School of Biological Sciences, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: Laura M
authors.initials: LM
authors.lastname: van Marrewijk
authors.affiliation: School of Biological Sciences, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Polyak
authors.affiliation: GE Healthcare Life Sciences ANZ , Melbourne, Victoria 3121, Australia.
authors.forename: Marcel
authors.initials: M
authors.lastname: Hijnen
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , Jupiter, Florida 33458, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Kuruvilla
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , Jupiter, Florida 33458, United States.
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Chang
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , Jupiter, Florida 33458, United States.
authors.forename: Youseung
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , Jupiter, Florida 33458, United States.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , Jupiter, Florida 33458, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: School of Biological Sciences, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: John B
authors.initials: JB
authors.lastname: Bruning
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism
chemical_list: D007211:Indoles; D047495:PPAR gamma; C000610592:SR2067; D013449:Sulfonamides