Response to Comment on Inhibition mechanism of NKCC1 involves the carboxyl terminus and long-range conformational coupling

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.

Automated summary

Moseng et al. recently reported four cryo-electron microscopy structures of the human Na-K-2Cl cotransporter-1 (hNKCC1), providing high-resolution structural information for both the apo-hNKCC1 structure and its conformational states induced by diuretic drugs. The authors proposed a scissor-like inhibition mechanism based on the structural information, involving coupled movement between the cytosolic and transmembrane domains of hNKCC1. This study has important implications for understanding the inhibition mechanism and the concept of long-distance coupling involving both cytoplasmic and transmembrane domains.