De novo variants in LRRC8C resulting in constitutive channel activation cause a human multisystem disorder.

Volume-regulated anion channels (VRACs) are multimeric proteins composed of different paralogs of the LRRC8 family. They are activated in response to hypotonic swelling, but little is known about their specific functions. We studied two human individuals with the same congenital syndrome affecting blood vessels, brain, eyes, and bones.

Structures of ferroportin in complex with its specific inhibitor vamifeport.

A central regulatory mechanism of iron homeostasis in humans involves ferroportin (FPN), the sole cellular iron exporter, and the peptide hormone hepcidin, which inhibits Fe transport and induces internalization and degradation of FPN. Dysregulation of the FPN/hepcidin axis leads to diverse pathological conditions, and consequently, pharmacological compounds that inhibit FPN-mediated iron transport are of high clinical interest. Here, we describe the cryo-electron microscopy structures of human FPN in complex with synthetic nanobodies and vamifeport (VIT-2763), the first clinical-stage oral FPN inhibitor.