5zbg

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Cryo-EM structure of human TRPC3 at 4.36A resolution

Structural highlights

5zbg is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[TRPC3_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.

Function

[TRPC3_HUMAN] Thought to form a receptor-activated non-selective calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C, and by inositol 1,4,5-triphosphate receptors (ITPR) with bound IP3. May also be activated by internal calcium store depletion.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

TRPC6 and TRPC3 are receptor-activated nonselective cation channels that belong to the family of canonical transient receptor potential (TRPC) channels. They are activated by diacylglycerol, a lipid second messenger. TRPC6 and TRPC3 are involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high-affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 A resolution. We also present the structure of human TRPC3 at 4.4 A resolution. These structures show two-layer architectures in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domains, including the N-terminal ankyrin repeats and the C-terminal coiled-coil, contribute to the tetramer assembly. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Our structures uncover the molecular architecture of TRPC channels and provide a structural basis for understanding the mechanism of these channels.

Structure of the receptor-activated human TRPC6 and TRPC3 ion channels.,Tang Q, Guo W, Zheng L, Wu JX, Liu M, Zhou X, Zhang X, Chen L Cell Res. 2018 Apr 26. pii: 10.1038/s41422-018-0038-2. doi:, 10.1038/s41422-018-0038-2. PMID:29700422^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Woo JS, Hwang JH, Ko JK, Weisleder N, Kim DH, Ma J, Lee EH. S165F mutation of junctophilin 2 affects Ca2+ signalling in skeletal muscle. Biochem J. 2010 Mar 15;427(1):125-34. doi: 10.1042/BJ20091225. PMID:20095964 doi:http://dx.doi.org/10.1042/BJ20091225
↑ Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, Birnbaumer L. trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell. 1996 May 31;85(5):661-71. PMID:8646775
↑ Zhu X, Jiang M, Birnbaumer L. Receptor-activated Ca2+ influx via human Trp3 stably expressed in human embryonic kidney (HEK)293 cells. Evidence for a non-capacitative Ca2+ entry. J Biol Chem. 1998 Jan 2;273(1):133-42. PMID:9417057
↑ Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature. 1999 Jan 21;397(6716):259-63. doi: 10.1038/16711. PMID:9930701 doi:http://dx.doi.org/10.1038/16711
↑ Tang Q, Guo W, Zheng L, Wu JX, Liu M, Zhou X, Zhang X, Chen L. Structure of the receptor-activated human TRPC6 and TRPC3 ion channels. Cell Res. 2018 Apr 26. pii: 10.1038/s41422-018-0038-2. doi:, 10.1038/s41422-018-0038-2. PMID:29700422 doi:http://dx.doi.org/10.1038/s41422-018-0038-2