7MBR

Cryo-EM structure of zebrafish TRPM5 in the presence of 6 uM calcium (apo state)

Summary for 7MBR

• Entry DOI: 10.2210/pdb7mbr/pdb
• EMDB information: 23740 23741 23742 23743 23744 23745 23746 23747 23748
• Descriptor: Transient receptor potential melastatin 5, 2-acetamido-2-deoxy-beta-D-glucopyranose, (25R)-14beta,17beta-spirost-5-en-3beta-ol, ... (4 entities in total)
• Functional Keywords: ion channel, trp channel, transport protein
• Biological source: Danio rerio (Zebrafish, Brachydanio rerio)
• Total number of polymer chains: 4
• Total formula weight: 537103.45

Authors

Ruan, Z.,Lu, W.,Du, J.,Haley, E. (deposition date: 2021-04-01, release date: 2021-07-07, Last modification date: 2024-10-09)

Primary citation

Ruan, Z.,Haley, E.,Orozco, I.J.,Sabat, M.,Myers, R.,Roth, R.,Du, J.,Lu, W.
Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition.
Nat.Struct.Mol.Biol., 28:604-613, 2021

PubMed Abstract: The Ca-activated TRPM5 channel plays essential roles in taste perception and insulin secretion. However, the mechanism by which Ca regulates TRPM5 activity remains elusive. We report cryo-EM structures of the zebrafish TRPM5 in an apo closed state, a Ca-bound open state, and an antagonist-bound inhibited state. We define two novel ligand binding sites: a Ca site (Ca) in the intracellular domain and an antagonist site in the transmembrane domain (TMD). The Ca site is unique to TRPM5 and has two roles: modulating the voltage dependence and promoting Ca binding to the Ca site, which is conserved throughout TRPM channels. Conformational changes initialized from both Ca sites cooperatively open the ion-conducting pore. The antagonist NDNA wedges into the space between the S1-S4 domain and pore domain, stabilizing the transmembrane domain in an apo-like closed state. Our results lay the foundation for understanding the voltage-dependent TRPM channels and developing new therapeutic agents.

PubMed: 34168372
DOI: 10.1038/s41594-021-00607-4

Experimental method

ELECTRON MICROSCOPY