7E4T

Human TRPC5 apo state structure at 3 angstrom

Summary for 7E4T

• Entry DOI: 10.2210/pdb7e4t/pdb
• EMDB information: 30987 9615
• Descriptor: Short transient receptor potential channel 5, PHOSPHATIDYLETHANOLAMINE, (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate, ... (7 entities in total)
• Functional Keywords: trpc5, trpc, metal transport
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 366119.42

Authors

Chen, L.,Song, K.,Wei, M.,Guo, W. (deposition date: 2021-02-15, release date: 2021-03-31, Last modification date: 2024-10-09)

Primary citation

Song, K.,Wei, M.,Guo, W.,Quan, L.,Kang, Y.,Wu, J.X.,Chen, L.
Structural basis for human TRPC5 channel inhibition by two distinct inhibitors.
Elife, 10:-, 2021

PubMed Abstract: TRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. However, the binding sites and inhibitory mechanism of TRPC5 inhibitors remain elusive. Here, we present the cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 Å. The structures reveal that clemizole binds inside the voltage sensor-like domain of each subunit. In contrast, HC-070 is wedged between adjacent subunits and replaces the glycerol group of a putative diacylglycerol molecule near the extracellular side. Moreover, we found mutations in the inhibitor binding pockets altered the potency of inhibitors. These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a nonconductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5.

PubMed: 33683200
DOI: 10.7554/eLife.63429

Experimental method

ELECTRON MICROSCOPY (3 Å)