7SQ9

Cryo-EM structure of mouse temsirolimus/PI(3,5)P2-bound TRPML1 channel at 2.11 Angstrom resolution

Summary for 7SQ9

• Entry DOI: 10.2210/pdb7sq9/pdb
• EMDB information: 25380
• Descriptor: Mucolipin-1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, (2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctanoate, ... (6 entities in total)
• Functional Keywords: ion channel, membrane protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 4
• Total formula weight: 271145.46

Authors

Gan, N.,Han, Y.,Jiang, Y. (deposition date: 2021-11-04, release date: 2022-02-02, Last modification date: 2024-10-16)

Primary citation

Gan, N.,Han, Y.,Zeng, W.,Wang, Y.,Xue, J.,Jiang, Y.
Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P 2 and rapamycin.
Proc.Natl.Acad.Sci.USA, 119:-, 2022

PubMed Abstract: Transient receptor potential mucolipin 1 (TRPML1) is a Ca-permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its loss-of-function mutations are the direct cause of type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease. TRPML1 is a ligand-gated channel that can be activated by phosphatidylinositol 3,5-bisphosphate [PI(3,5)P] as well as some synthetic small-molecule agonists. Recently, rapamycin has also been shown to directly bind and activate TRPML1. Interestingly, both PI(3,5)P and rapamycin have low efficacy in channel activation individually but together they work cooperatively and activate the channel with high potency. To reveal the structural basis underlying the synergistic activation of TRPML1 by PI(3,5)P and rapamycin, we determined the high-resolution cryoelectron microscopy (cryo-EM) structures of the mouse TRPML1 channel in various states, including apo closed, PI(3,5)P-bound closed, and PI(3,5)P/temsirolimus (a rapamycin analog)-bound open states. These structures, combined with electrophysiology, elucidate the molecular details of ligand binding and provide structural insight into how the TRPML1 channel integrates two distantly bound ligand stimuli and facilitates channel opening.

PubMed: 35131932
DOI: 10.1073/pnas.2120404119

Experimental method

ELECTRON MICROSCOPY (2.11 Å)