7LOT

Human PPAR Gamma LBD in Complex with Tetrazole Compound N-{3-[(4-methylbenzyl)oxy]benzyl}-2H-tetrazol-5-amine.

7LOT の概要

• エントリーDOI: 10.2210/pdb7lot/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, ~{N}-[[3-[(4-methylphenyl)methoxy]phenyl]methyl]-1~{H}-1,2,3,4-tetrazol-5-amine (3 entities in total)
• 機能のキーワード: ppar gamma, complex, tetrazole, gene regulation
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64060.40

構造登録者

de Paula, K.,Nascimento, A.S. (登録日: 2021-02-10, 公開日: 2021-02-24, 最終更新日: 2023-10-18)

主引用文献

de Paula, K.,Santos, J.C.,Mafud, A.C.,Nascimento, A.S.
Tetrazoles as PPAR gamma ligands: A structural and computational investigation.
J.Mol.Graph.Model., 106:107932-107932, 2021

PubMed Abstract: Diabetes is an important chronic disease affecting about 10% of the adult population in the US and over 420 million people worldwide, resulting in 1.6 million deaths every year, according to the World Health Organization. The most common type of the disease, type 2 diabetes, can be pharmacologically managed using oral hypoglycemic agents or thiazolidinediones (TZDs), such as pioglitazone, which act by activating the Peroxisome Proliferated-Activated Receptor γ. Despite their beneficial effects in diabetes treatment, TZDs like rosiglitazone and troglitazone were withdrawn due to safety reasons, creating a void in the pharmacological options for the treatment of this important disease. Here, we explored a structure-based approach in the screening for new chemical probes for a deeper investigation of the effects of PPARγ activation. A class of tetrazole compounds was identified and the compounds named T1, T2 and T3 were purchased and evaluated for their ability to interact with the PPARγ ligand binding domain (LBD). The compounds were binders with micromolar range affinity, as determined by their IC values. A Monte Carlo simulation of the compound T2 revealed that the tetrazole ring makes favorable interaction with the polar arm of the receptor binding pocket. Finally, the crystal structure of the PPARγ-LBD-T2 complex was solved at 2.3 Å, confirming the binding mode for this compound. The structure also revealed that, when the helix H12 is mispositioned, an alternative binding conformation is observed for the ligand suggesting an H12-dependent binding conformation for the tetrazole compound.

PubMed: 33946041
DOI: 10.1016/j.jmgm.2021.107932

実験手法

X-RAY DIFFRACTION (2.29 Å)