Atomic insights into ML-SI3 mediated human TRPML1 inhibition.
Atomic insights into ML-SI3 mediated human TRPML1 inhibition.
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DOI：
10.1016/j.str.2021.06.003
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发表时间：
2021-11-04
期刊：
影响因子：
--
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Schmiege P;Fine M;Li X
瞬时受体电位粘磷脂1 （TRPML1）调节溶酶体钙信号、脂质运输和自噬相关过程。该通道受磷酸肌苷和溶酶体的低pH环境调节，维持溶酶体正常功能所必需的钙水平。最近，一些专门针对TRPML家族的小分子已被证明可以调节通道活性。其中一种是合成拮抗剂ML-SI3，它可以阻止溶酶体钙外排，并且据报道可以阻断下游trpml1介导的自噬诱导。在这里，我们报告了一个含有ML-SI3的人TRPML1的低温电镜结构，分辨率为2.9-Å。ML-SI3结合到由S5、S6和PH1形成的疏水空腔上，与合成激动剂ML-SA1结合的空腔相同。电生理表征表明ML-SI3可以与ML-SA1竞争，阻断通道激活，但不抑制PI(3,5)P2依赖的通道激活。因此，这项工作为ML-SI3和天然脂质如何调节TRPML1活性提供了分子视角。Schmiege等人在先前解决的TRPML1结构的基础上，报道了TRPML1与合成抑制剂ML-SI3结合的结构，该抑制剂与合成激动剂ML-SA1结合在相同的位点。电生理实验表明，ML-SI3可以影响ML-SA1的激活，但不影响天然脂质激动剂PI(3,5)P2的激活。
Transient receptor potential mucolipin 1 (TRPML1) regulates lysosomal calcium signaling, lipid trafficking and autophagy-related processes. This channel is regulated by phosphoinositides and the low pH environment of the lysosome, maintaining calcium levels essential for proper lysosomal function. Recently, several small molecules specifically targeting the TRPML family have been demonstrated to modulate channel activity. One of these, a synthetic antagonist ML-SI3, can prevent lysosomal calcium efflux and has been reported to block downstream TRPML1-mediated induction of autophagy. Here, we report a cryo-EM structure of human TRPML1 with ML-SI3 at 2.9-Å resolution. ML-SI3 binds to the hydrophobic cavity created by S5, S6 and PH1, the same cavity where the synthetic agonist ML-SA1 binds. Electrophysiological characterizations show that ML-SI3 can compete with ML-SA1, blocking channel activation yet does not inhibit PI(3,5)P2 dependent activation of the channel. Consequently, this work provides molecular insight into how ML-SI3 and native lipids regulate TRPML1 activity. Building on the previously solved TRPML1 structures, Schmiege et al. report the structure of TRPML1 bound to the synthetic inhibitor ML-SI3, which binds to the same site as the synthetic agonist ML-SA1. Electrophysiology experiments show that ML-SI3 can affect ML-SA1 activation but not activation by the native lipid agonist PI(3,5)P2.
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影响因子：
16.6
作者：
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DOI：
10.1085/jgp.201010469
发表时间：
2011-02
期刊：
The Journal of general physiology
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影响因子：
16.8
作者：
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通讯作者：
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