Structural highlights
7d4q is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , , , , |
| Gene: | TRPC5, TRP5 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[TRPC5_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. Has also been shown to be calcium-selective (By similarity). May also be activated by intracellular calcium store depletion. Mediates calcium-dependent phosphatidylserine externalization and apoptosis in neurons via its association with PLSCR1 (By similarity).[UniProtKB:Q9QX29][1]
Publication Abstract from PubMed
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 A. 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.
Structural basis for human TRPC5 channel inhibition by two distinct inhibitors.,Song K, Wei M, Guo W, Quan L, Kang Y, Wu JX, Chen L Elife. 2021 Mar 8;10. pii: 63429. doi: 10.7554/eLife.63429. PMID:33683200[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shimizu S, Yoshida T, Wakamori M, Ishii M, Okada T, Takahashi M, Seto M, Sakurada K, Kiuchi Y, Mori Y. Ca2+-calmodulin-dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK293 cells. J Physiol. 2006 Jan 15;570(Pt 2):219-35. Epub 2005 Nov 10. PMID:16284075 doi:10.1113/jphysiol.2005.097998
- ↑ Song K, Wei M, Guo W, Quan L, Kang Y, Wu JX, Chen L. Structural basis for human TRPC5 channel inhibition by two distinct inhibitors. Elife. 2021 Mar 8;10. pii: 63429. doi: 10.7554/eLife.63429. PMID:33683200 doi:http://dx.doi.org/10.7554/eLife.63429
