9EKY

(+)ML-SI3 bound TRPML2 in a pre-open state

Summary for 9EKY

• Entry DOI: 10.2210/pdb9eky/pdb
• EMDB information: 48141
• Descriptor: Mucolipin-2, N-{(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide (2 entities in total)
• Functional Keywords: trpml, calcium channel, ion transport, cryo-em, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 265783.49

Authors

Schmiege, P.,Li, X. (deposition date: 2024-12-03, release date: 2025-06-18, Last modification date: 2026-01-07)

Primary citation

Schmiege, P.,Jaslan, D.,Fine, M.,Sadanandan, N.P.,Hatton, A.,Elghobashi-Meinhardt, N.,Grimm, C.,Li, X.
TRPML2 in distinct states reveals the activation and modulation principles of the TRPML family.
Nat Commun, 16:5325-5325, 2025

PubMed Abstract: TRPML2 activity is critical for endolysosomal integrity and chemokine secretion, and can be modulated by various ligands. Interestingly, two ML-SI3 isomers regulate TRPML2 oppositely. The molecular mechanism underlying this unique isomeric preference as well as the TRPML2 agonistic mechanism remains unknown. Here, we present six cryo-EM structures of human TRPML2 in distinct states revealing that the π-bulge of the S6 undergoes a π-α transition upon agonist binding, highlighting the remarkable role of the π-bulge in ion channel regulation. Moreover, we identify that PI(3,5)P allosterically affects the pose of ML2-SA1, a TRPML2 specific activator, resulting in an open channel without the π-α transition. Functional and structural studies show that mutating the S5 of TRPML1 to that of TRPML2 enables the mutated TRPML1 to be activated by (+)ML-SI3 and ML2-SA1. Thus, our work elucidates the activation mechanism of TRPML channels and paves the way for the development of selective TRPML modulators.

PubMed: 40527873
DOI: 10.1038/s41467-025-60710-8

Experimental method

ELECTRON MICROSCOPY (2.67 Å)