7MGL

Structure of human TRPML1 with ML-SI3

Summary for 7MGL

• Entry DOI: 10.2210/pdb7mgl/pdb
• EMDB information: 23828
• Descriptor: Mucolipin-1, N-{(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide, 1,2-Distearoyl-sn-glycerophosphoethanolamine (3 entities in total)
• Functional Keywords: trpml, calcium, ml-si3, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 265050.55

Authors

Schmiege, P.,Li, X. (deposition date: 2021-04-12, release date: 2021-06-16, Last modification date: 2024-10-16)

Primary citation

Schmiege, P.,Fine, M.,Li, X.
Atomic insights into ML-SI3 mediated human TRPML1 inhibition.
Structure, 29:1295-1302.e3, 2021

PubMed Abstract: 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.

PubMed: 34171299
DOI: 10.1016/j.str.2021.06.003

Experimental method

ELECTRON MICROSCOPY (2.9 Å)