7WOX

PPARgamma antagonist (MMT-160)- PPARgamma LBD complex

Summary for 7WOX

• Entry DOI: 10.2210/pdb7wox/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, N-[[5-(3-phenylprop-2-ynoylamino)-2-propoxy-phenyl]methyl]-4-pyrimidin-2-yl-benzamide (3 entities in total)
• Functional Keywords: ppargamma, mtt160, covalent modifier, nuclear hormone receptor, antagonist, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 63389.59

Authors

Yoshizawa, M.,Aoyama, T.,Itoh, T.,Miyachi, H. (deposition date: 2022-01-22, release date: 2022-04-13, Last modification date: 2024-10-30)

Primary citation

Yoshizawa, M.,Aoyama, T.,Itoh, T.,Miyachi, H.
Arylalkynyl amide-type peroxisome proliferator-activated receptor gamma (PPAR gamma )-selective antagonists covalently bind to the PPAR gamma ligand binding domain with a unique binding mode.
Bioorg.Med.Chem.Lett., 64:128676-128676, 2022

PubMed Abstract: Peroxisome proliferator-activated receptor γ (PPARγ) antagonists are drug candidates for the treatment of type 2 diabetes, obesity, and osteoporosis. Previously, we have designed and synthesized a series of substituted phenylalkynyl amide-type PPARγ antagonists. The representative compound, MMT-160, exhibited nanomolar-order PPARγ antagonistic activity. To understand the antagonistic mode of action of MMT-160, mass spectrometric and X-ray crystallographic analysis of MMT-160 in the presence of the PPARγ ligand binding domain (LBD) were performed. The mass spectrometry results clearly indicated that alkynyl amide-type PPARγ antagonists were covalently bound to the PPARγ LBD. The X-ray crystallographic analysis indicated that MMT-160 acted as a Michael acceptor and covalently bound to the PPARγ LBD via Cys285. In addition, MMT-160 bound to the PPARγ LBD with a binding mode that was different from the binding modes observed for PPARγ agonists and partial agonists.

PubMed: 35301139
DOI: 10.1016/j.bmcl.2022.128676

Experimental method

X-RAY DIFFRACTION (3.2 Å)