National Institutes of Health/National Center for Research Resources (NIH/NCRR)
R01GM071940/AI094386/DE025567
米国
National Institutes of Health/National Center for Research Resources (NIH/NCRR)
R01DK46917/DK53462/DK58333
米国
引用
ジャーナル: Sci Adv / 年: 2019 タイトル: pH-dependent gating mechanism of the urea channel revealed by cryo-EM. 著者: Yanxiang Cui / Kang Zhou / David Strugatsky / Yi Wen / George Sachs / Z Hong Zhou / Keith Munson / 要旨: The urea channel of (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 . ...The urea channel of (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 . Here, we present the cryo-EM structures of 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 eradication.