7m19 | pdb_00007m19
SN-407-LRRC8A in MSP1E3D1 lipid nanodiscs (Pose-2)
Structural highlights
Function[LRC8A_MOUSE] Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes. The VRAC channel conducts iodide better than chloride and may also conduct organic osmolytes like taurine. Required for channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition. Can form functional channels by itself (in vitro) (By similarity). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746, PubMed:24752297). Also required for T-cell development (PubMed:24752297).[UniProtKB:Q8IWT6][1] [2] Publication Abstract from PubMedType 2 diabetes is associated with insulin resistance, impaired pancreatic beta-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs beta-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and beta-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. Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes.,Gunasekar SK, Xie L, Kumar A, Hong J, Chheda PR, Kang C, Kern DM, My-Ta C, Maurer J, Heebink J, Gerber EE, Grzesik WJ, Elliot-Hudson M, Zhang Y, Key P, Kulkarni CA, Beals JW, Smith GI, Samuel I, Smith JK, Nau P, Imai Y, Sheldon RD, Taylor EB, Lerner DJ, Norris AW, Klein S, Brohawn SG, Kerns R, Sah R Nat Commun. 2022 Feb 10;13(1):784. doi: 10.1038/s41467-022-28435-0. PMID:35145074[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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