6AYF

TRPML3/ML-SA1 complex at pH 7.4

Summary for 6AYF

• Entry DOI: 10.2210/pdb6ayf/pdb
• EMDB information: 7018 7019 7020
• Descriptor: Mucolipin-3, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• Functional Keywords: ion channel, trp channel, lysosomal, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 260272.80

Authors

Zhou, X.,Li, M.,Su, D.,Jia, Q.,Li, H.,Li, X.,Yang, J. (deposition date: 2017-09-08, release date: 2017-11-08, Last modification date: 2024-11-20)

Primary citation

Zhou, X.,Li, M.,Su, D.,Jia, Q.,Li, H.,Li, X.,Yang, J.
Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states.
Nat. Struct. Mol. Biol., 24:1146-1154, 2017

PubMed Abstract: 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 PIP regulate TRPML3 by changing S1 and S2 conformations.

PubMed: 29106414
DOI: 10.1038/nsmb.3502

Experimental method

ELECTRON MICROSCOPY (3.62 Å)