3VSO

Human PPAR gamma ligand binding domain in complex with a gamma selective agonist mekt21

Summary for 3VSO

• Entry DOI: 10.2210/pdb3vso/pdb
• Related: 3VSP 3an3
• Descriptor: Peroxisome proliferator-activated receptor gamma, (2R)-2-benzyl-3-[4-propoxy-3-({[4-(pyrimidin-2-yl)benzoyl]amino}methyl)phenyl]propanoic acid (3 entities in total)
• Functional Keywords: mainly alpha, nuclear receptor, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 65570.90

Authors

Oyama, T.,Waku, T.,Ohashi, M.,Morikawa, K.,Miyachi, H. (deposition date: 2012-04-30, release date: 2013-05-01, Last modification date: 2023-11-08)

Primary citation

Ohashi, M.,Oyama, T.,Putranto, E.W.,Waku, T.,Nobusada, H.,Kataoka, K.,Matsuno, K.,Yashiro, M.,Morikawa, K.,Huh, N.H.,Miyachi, H.
Design and synthesis of a series of alpha-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility
Bioorg.Med.Chem., 21:2319-2332, 2013

PubMed Abstract: In the continuing study directed toward the development of peroxisome proliferator-activated receptor gamma (hPPARγ) agonist, we attempted to improve the water solubility of our previously developed hPPARγ-selective agonist 3, which is insufficiently soluble for practical use, by employing two strategies: introducing substituents to reduce its molecular planarity and decreasing its hydrophobicity via replacement of the adamantyl group with a heteroaromatic ring. The first approach proved ineffective, but the second was productive. Here, we report the design and synthesis of a series of α-benzyl phenylpropanoic acid-type hPPARγ partial agonists with improved aqueous solubility. Among them, we selected (R)-7j, which activates hPPARγ to the extent of about 65% of the maximum observed with a full agonist, for further evaluation. The ligand-binding mode and the reason for the partial-agonistic activity are discussed based on X-ray-determined structure of the complex of hPPARγ ligand-binding domain (LBD) and (R)-7j with previously reported ligand-LDB structures. Preliminal apoptotic effect of (R)-7j against human scirrhous gastric cancer cell line OCUM-2MD3 is also described.

PubMed: 23490155
DOI: 10.1016/j.bmc.2013.02.003

Experimental method

X-RAY DIFFRACTION (2 Å)