7DXG

Structure of SAR7334-bound TRPC6 at 2.9 angstrom

Summary for 7DXG

• Entry DOI: 10.2210/pdb7dxg/pdb
• EMDB information: 30908
• Descriptor: Short transient receptor potential channel 6, ZINC ION, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: trpc6, trpc, fsgs, sar7334, channel, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 441178.58

Authors

Chen, L.,Guo, W. (deposition date: 2021-01-18, release date: 2022-02-02, Last modification date: 2024-06-05)

Primary citation

Guo, W.,Tang, Q.,Wei, M.,Kang, Y.,Wu, J.X.,Chen, L.
Structural mechanism of human TRPC3 and TRPC6 channel regulation by their intracellular calcium-binding sites.
Neuron, 110:1023-1035.e5, 2022

PubMed Abstract: TRPC3 and TRPC6 channels are calcium-permeable non-selective cation channels that are involved in many physiological processes. The gain-of-function (GOF) mutations of TRPC6 lead to familial focal segmental glomerulosclerosis (FSGS) in humans, but their pathogenic mechanism remains elusive. Here, we report the cryo-EM structures of human TRPC3 in both high-calcium and low-calcium conditions. Based on these structures and accompanying electrophysiological studies, we identified both inhibitory and activating calcium-binding sites in TRPC3 that couple intracellular calcium concentrations to the basal channel activity. These calcium sensors are also structurally and functionally conserved in TRPC6. We uncovered that the GOF mutations of TRPC6 activate the channel by allosterically abolishing the inhibitory effects of intracellular calcium. Furthermore, structures of human TRPC6 in complex with two chemically distinct inhibitors bound at different ligand-binding pockets reveal different conformations of the transmembrane domain, providing templates for further structure-based drug design targeting TRPC6-related diseases such as FSGS.

PubMed: 35051376
DOI: 10.1016/j.neuron.2021.12.023

Experimental method

ELECTRON MICROSCOPY (2.9 Å)