TRPML3 channels are mainly localized to endolysosomes and play a critical role in the endocytic pathway. Their dysfunction causes deafness and pigmentation defects in mice. TRPML3 activity is inhibited by low endolysosomal pH. Here we present cryo-electron microscopy (cryo-EM) structures of human TRPML3 in the closed, agonist-activated, and low-pH-inhibited states, with resolutions of 4.06, 3.62, and 4.65 Å, respectively. The agonist ML-SA1 lodges between S5 and S6 and opens an S6 gate. A polycystin-mucolipin domain (PMD) forms a luminal cap. S1 extends into this cap, forming a 'gating rod' that connects directly to a luminal pore loop, which undergoes dramatic conformational changes in response to low pH. S2 extends intracellularly and interacts with several intracellular regions to form a 'gating knob'. These unique structural features, combined with the results of electrophysiological studies, indicate a new mechanism by which luminal pH and other physiological modulators such as PIP₂ regulate TRPML3 by changing S1 and S2 conformations.

中文翻译：

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人溶酶体TRPML3通道的低温EM结构处于三种不同状态

TRPML3通道主要位于溶酶体，并在胞吞途径中起关键作用。它们的功能障碍导致小鼠耳聋和色素沉着缺陷。低的溶酶体pH抑制TRPML3的活性。在这里，我们介绍了处于闭合，激动剂激活和低pH抑制状态的人TRPML3的低温电子显微镜（cryo-EM）结构，其分辨率分别为4.06、3.62和4.65Å。激动剂ML-SA1位于S5和S6之间，并打开S6门。多囊蛋白-粘蛋白域（PMD）形成管腔帽。S1延伸到该盖中，形成直接连接至腔孔环的“门控杆”，该门环会响应低pH发生剧烈的构象变化。S2在细胞内延伸并与几个细胞内区域相互作用以形成“门控旋钮”。₂通过更改S1和S2构象来调节TRPML3。