Response to Comment on “Inhibition mechanism of NKCC1 involves the carboxyl terminus and long-range conformational coupling” | Science Advances

Moseng et al. recently reported four cryo–electron microscopy structures of the human Na-K-2Cl cotransporter-1 (hNKCC1), both in the absence and presence of bound loop diuretic (furosemide or bumetanide). This research article included high-resolution structural information for a previously undefined structure of apo-hNKCC1 containing both the transmembrane and cytosolic carboxyl-terminal domains. The manuscript also demonstrated various conformational states of this cotransporter induced by diuretic drugs. On the basis of the structural information, the authors proposed a scissor-like inhibition mechanism that involves a coupled movement between the cytosolic and transmembrane domains of hNKCC1. This work has provided important insights into the mechanism of inhibition and substantiated the concept of a long-distance coupling involving movements of both the transmembrane and carboxyl-terminal cytoplasmic domains for inhibition.