Molecular Basis of CLC Antiporter Inhibition by Fluoride
Molecular Basis of CLC Antiporter Inhibition by Fluoride
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DOI：
10.1021/jacs.9b13588
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发表时间：
2020-04-22
影响因子：
15
通讯作者：
Carloni, Paolo
中科院分区：
文献类型：
--
作者：
Chiariello, Maria Gabriella;Bolnykh, Viacheslav;Carloni, Paolo
CLC通道和转运蛋白传导或转运各种阴离子，但氟离子除外，氟离子是一种有效的抑制剂。在这里，我们进行了亚纳秒基于DFT的QM/MM模拟的E。coli阴离子/质子交换剂ClC-ec 1，并观察到氟化物在选择性过滤器内结合进入的质子，过量的质子与门控谷氨酸E148共享。根据E148构象，质子的竞争可能涉及直接的F-/E148相互作用或调节桥接两种阴离子的水分子。直接相互作用将E148锁定在不允许质子转运的构象中，从而抑制蛋白质功能。
CLC channels and transporters conduct or transport various kinds of anions, with the exception of fluoride, which acts as an effective inhibitor. Here, we performed sub-nanosecond DFT-based QM/MM simulations of the E. coli anion/proton exchanger ClC-ec1 and observed that fluoride binds incoming protons within the selectivity filter, with excess protons shared with the gating glutamate E148. Depending on E148 conformation, the competition for the proton can involve either a direct F-/E148 interaction or the modulation of water molecules bridging the two anions. The direct interaction locks E148 in a conformation that does not allow for proton transport, and thus inhibits protein function.