8DHM

Human TMEM175 in complex with 4-aminopyridine

Summary for 8DHM

• Entry DOI: 10.2210/pdb8dhm/pdb
• EMDB information: 27436
• Descriptor: Endosomal/lysosomal potassium channel TMEM175, POTASSIUM ION, 4-AMINOPYRIDINE, ... (4 entities in total)
• Functional Keywords: potassium channel, ion channel, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 111585.95

Authors

Oh, S.,Hite, R.K. (deposition date: 2022-06-27, release date: 2022-11-23, Last modification date: 2024-06-12)

Primary citation

Oh, S.,Stix, R.,Zhou, W.,Faraldo-Gomez, J.D.,Hite, R.K.
Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175.
Proc.Natl.Acad.Sci.USA, 119:e2208882119-e2208882119, 2022

PubMed Abstract: Transmembrane protein 175 (TMEM175) is an evolutionarily distinct lysosomal cation channel whose mutation is associated with the development of Parkinson's disease. Here, we present a cryoelectron microscopy structure and molecular simulations of TMEM175 bound to 4-aminopyridine (4-AP), the only known small-molecule inhibitor of TMEM175 and a broad K channel inhibitor, as well as a drug approved by the Food and Drug Administration against multiple sclerosis. The structure shows that 4-AP, whose mode of action had not been previously visualized, binds near the center of the ion conduction pathway, in the open state of the channel. Molecular dynamics simulations reveal that this binding site is near the middle of the transmembrane potential gradient, providing a rationale for the voltage-dependent dissociation of 4-AP from TMEM175. Interestingly, bound 4-AP rapidly switches between three predominant binding poses, stabilized by alternate interaction patterns dictated by the twofold symmetry of the channel. Despite this highly dynamic binding mode, bound 4-AP prevents not only ion permeation but also water flow. Together, these studies provide a framework for the rational design of novel small-molecule inhibitors of TMEM175 that might reveal the role of this channel in human lysosomal physiology both in health and disease.

PubMed: 36279431
DOI: 10.1073/pnas.2208882119

Experimental method

ELECTRON MICROSCOPY (2.73 Å)