4R06

Crystal Structure of SR2067 bound to PPARgamma

Summary for 4R06

• Entry DOI: 10.2210/pdb4r06/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 1-(naphthalen-1-ylsulfonyl)-N-[(1S)-1-phenylpropyl]-1H-indole-5-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: nuclear receptor, ligand binding protein, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 62981.10

Authors

Marrewijk, L.,Kamenecka, T.,Griffin, P.R.,Bruning, J.B. (deposition date: 2014-07-30, release date: 2016-01-27, Last modification date: 2023-09-20)

Primary citation

van Marrewijk, L.M.,Polyak, S.W.,Hijnen, M.,Kuruvilla, D.,Chang, M.R.,Shin, Y.,Kamenecka, T.M.,Griffin, P.R.,Bruning, J.B.
SR2067 Reveals a Unique Kinetic and Structural Signature for PPAR gamma Partial Agonism.
Acs Chem.Biol., 11:273-283, 2016

PubMed 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.

PubMed: 26579553
DOI: 10.1021/acschembio.5b00580

Experimental method

X-RAY DIFFRACTION (2.22 Å)