Structural basis for differential activities of enantiomeric PPARγ agonists: Binding of S35 to the alternate site.
Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte differentiation, type 2 diabetes mellitus, and inflammation. Many PPARγ agonists bind to the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i.e., helix H12) of the ligand-binding domain (LBD). More recently, an alternate ligand-binding site was identified in PPARγ LBD; it is located beside the Ω loop between the helices H2' and H3. We reported previously that the chirality of two optimized enantiomeric PPARγ ligands (S35 and R35) differentiates their PPARγ transcriptional activity, binding affinity, and inhibitory activity toward Cdk5 (cyclin-dependent kinase 5)-mediated phosphorylation of PPARγ at Ser245 (in PPARγ1 numbering; Ser273 in PPARγ2 numbering). S35 is a PPARγ phosphorylation inhibitor with promising glucose uptake potential, whereas R35 behaves as a potent conventional PPARγ agonist. To provide a structural basis for understanding the differential activities of these enantiomeric ligands, we have determined crystal structures of the PPARγ LBD in complex with either S35 or R35. S35 and R35 bind to the PPARγ LBD in significantly different manners. The partial agonist S35 occupies the alternate site near the Ω loop, whereas the full agonist R35 binds entirely to the canonical LBP. Alternate site binding of S35 affects the PPARγ transactivation and the inhibitory effect on PPARγ Ser245 phosphorylation. This study provides a useful platform for the development of a new generation of PPARγ ligands as anti-diabetic drug candidates.
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Jun Young
JY
Jang
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Minseob
M
Koh
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Hwan
H
Bae
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Doo Ri
DR
An
Biomolecular Function Research Branch, Division of Precision Medicine and Cancer Informatics, Research Institute, National Cancer Center, Gyeonggi 10408, Republic of Korea.
Ha Na
HN
Im
Biomolecular Function Research Branch, Division of Precision Medicine and Cancer Informatics, Research Institute, National Cancer Center, Gyeonggi 10408, Republic of Korea.
Hyoun Sook
HS
Kim
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Ji Young
JY
Yoon
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Hye-Jin
HJ
Yoon
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Byung Woo
BW
Han
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Seung Bum
SB
Park
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: sewonsuh@snu.ac.kr.
Se Won
SW
Suh
D001665:Binding Sites; D018360:Crystallography, X-Ray; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones
Alternate ligand-binding site; Crystal structure; PPARγ agonist; Peroxisome proliferator-activated receptor; Type 2 diabetes; Ω loop