7M17

SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-1)

7M17 の概要

• エントリーDOI: 10.2210/pdb7m17/pdb
• EMDBエントリー: 23614
• 分子名称: Volume-regulated anion channel subunit LRRC8A, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 7-{[(2S)-2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl]oxy}heptanoic acid (3 entities in total)
• 機能のキーワード: ion channel, inhibitor, membrane protein
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 585407.10

構造登録者

Kern, D.M.,Gerber, E.E.,Brohawn, S.G. (登録日: 2021-03-12, 公開日: 2021-03-24, 最終更新日: 2026-03-04)

主引用文献

Gunasekar, S.K.,Xie, L.,Kumar, A.,Hong, J.,Chheda, P.R.,Kang, C.,Kern, D.M.,My-Ta, C.,Maurer, J.,Heebink, J.,Gerber, E.E.,Grzesik, W.J.,Elliot-Hudson, M.,Zhang, Y.,Key, P.,Kulkarni, C.A.,Beals, J.W.,Smith, G.I.,Samuel, I.,Smith, J.K.,Nau, P.,Imai, Y.,Sheldon, R.D.,Taylor, E.B.,Lerner, D.J.,Norris, A.W.,Klein, S.,Brohawn, S.G.,Kerns, R.,Sah, R.
Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes.
Nat Commun, 13:784-784, 2022

PubMed Abstract: Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that I and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.

PubMed: 35145074
DOI: 10.1038/s41467-022-28435-0

実験手法

ELECTRON MICROSCOPY (3.65 Å)