7M19
SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)
Summary for 7M19
| Entry DOI | 10.2210/pdb7m19/pdb |
| Related | 7M17 |
| EMDB information | 23614 23616 |
| Descriptor | 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) |
| Functional Keywords | ion channel, inhibitor, membrane protein |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 6 |
| Total formula weight | 585407.10 |
| Authors | Kern, D.M.,Gerber, E.E.,Brohawn, S.G. (deposition date: 2021-03-12, release date: 2021-03-24, Last modification date: 2022-02-23) |
| Primary citation | 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 Cited by 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: 35145074DOI: 10.1038/s41467-022-28435-0 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.69 Å) |
Structure validation
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