pH-dependent gating mechanism of the <i>Helicobacter pylori</i> urea channel revealed by cryo-EM.

Abstract

The urea channel of <i>Helicobacter</i> <i>pylori</i> (<i>Hp</i>UreI) is an ideal drug target for preventing gastric cancer but incomplete understanding of its gating mechanism has hampered development of inhibitors for the eradication of <i>H. pylori</i>. Here, we present the cryo-EM structures of <i>Hp</i>UreI in closed and open conformations, both at a resolution of 2.7 Å. Our hexameric structures of this small membrane protein (~21 kDa/protomer) resolve its periplasmic loops and carboxyl terminus that close and open the channel, and define a gating mechanism that is pH dependent and requires cooperativity between protomers in the hexamer. Gating is further associated with well-resolved changes in the channel-lining residues that modify the shape and length of the urea pore. Site-specific mutations in the periplasmic domain and urea pore identified key residues important for channel function. Drugs blocking the urea pore based on our structures should lead to a new strategy for <i>H. pylori</i> eradication.