TY - JOUR
T1 - Peroxisome proliferator-activated receptor gamma (PPARγ) has multiple binding points that accommodate ligands in various conformations
T2 - Structurally similar PPARγ partial agonists bind to PPARγ LBD in different conformations
AU - Ohashi, Masao
AU - Gamo, Kanae
AU - Oyama, Takuji
AU - Miyachi, Hiroyuki
N1 - Funding Information:
This work was supported in part by a grant for Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and a Grant in-aid for Scientific Research (B) (grant number 26293027 to H.M.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). We also thank the SC-NMR Laboratory of Okayama University for NMR measurements.
Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2015/6/4
Y1 - 2015/6/4
N2 - In the course of studies directed toward the creation of human peroxisome proliferator-activated receptor gamma (hPPARγ) partial agonists, we designed and synthesized benzylsulfonylaminocarbonyl derivative (3) by structural modification of our reported hPPARγ partial agonist 2. Co-crystallization of 3 with the hPPARγ ligand-binding domain (LBD) afforded a homodimeric complex in which one of the LBDs adopts a fully active structure without bound 3, while the other LBD exhibits a non-fully active structure containing one molecule of bound 3. Interestingly, 2 and 3 are structurally similar, but bind to hPPARγ LBD in distinct conformations, that is, the sulfonylaminocarbonyl moiety of bound 3 is directed at 180°away from that of bound 2. These results support our previous proposal that the hPPARγ LBD has multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands.
AB - In the course of studies directed toward the creation of human peroxisome proliferator-activated receptor gamma (hPPARγ) partial agonists, we designed and synthesized benzylsulfonylaminocarbonyl derivative (3) by structural modification of our reported hPPARγ partial agonist 2. Co-crystallization of 3 with the hPPARγ ligand-binding domain (LBD) afforded a homodimeric complex in which one of the LBDs adopts a fully active structure without bound 3, while the other LBD exhibits a non-fully active structure containing one molecule of bound 3. Interestingly, 2 and 3 are structurally similar, but bind to hPPARγ LBD in distinct conformations, that is, the sulfonylaminocarbonyl moiety of bound 3 is directed at 180°away from that of bound 2. These results support our previous proposal that the hPPARγ LBD has multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands.
KW - PPAR
KW - Partial agonist
KW - Peroxisome proliferator-activated receptor
KW - X-ray
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U2 - 10.1016/j.bmcl.2015.05.025
DO - 10.1016/j.bmcl.2015.05.025
M3 - Article
AN - SCOPUS:84930276296
VL - 25
SP - 2758
EP - 2762
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 14
ER -