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-Structure paper
タイトル | Atomic insights into ML-SI3 mediated human TRPML1 inhibition. |
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ジャーナル・号・ページ | Structure, Vol. 29, Issue 11, Page 1295-11302.e3, Year 2021 |
掲載日 | 2021年11月4日 |
著者 | Philip Schmiege / Michael Fine / Xiaochun Li / |
PubMed 要旨 | 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 ...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-electron microscopy 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)P-dependent activation of the channel. Consequently, this work provides molecular insight into how ML-SI3 and native lipids regulate TRPML1 activity. |
リンク | Structure / PubMed:34171299 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.9 Å |
構造データ | EMDB-23828, PDB-7mgl: |
化合物 | ChemComp-ZB4: ChemComp-3PE: |
由来 |
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キーワード | MEMBRANE PROTEIN / TRPML / Calcium / ML-SI3 |