Electron cryo-microscopy structure of the canonical TRPC4 ion channel

Vinayagam, Deivanayagabarathy; Mager, Thomas; Apelbaum, Amir; Bothe, Arne; Merino, Felipe; Hofnagel, Oliver; Gatsogiannis, Christos; Raunser, Stefan

doi:10.1101/280503

Cited by 27 publications

(55 citation statements)

References 72 publications

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“…In the past few years, the resolution revolution in cryo‐electron microscopy brought several high‐resolution structures of TRP channels. Recently, two different groups solved the electron cryo‐microscopy structure of the TRPC4 ion channel (Duan et al, ; Vinayagam et al, ). Vinayagam et al () reported a structure of mouse TRPC4 in its apo state to an overall resolution of 3.3 Å.…”

Section: Future Directionsmentioning

confidence: 99%

“…Recently, two different groups solved the electron cryo‐microscopy structure of the TRPC4 ion channel (Duan et al, ; Vinayagam et al, ). Vinayagam et al () reported a structure of mouse TRPC4 in its apo state to an overall resolution of 3.3 Å. The comparison of the mouse TRPC4 structure with other TRP channel structures solved earlier (human TRPM4, mouse TRPV1, human TRPA1, human TRPP1, and mouse TRP mucolipin 1) revealed similarities as expected (Duan et al, ).…”

Section: Future Directionsmentioning

confidence: 99%

“…The TRPC4 organization of six helices in each transmembrane domain is comparable to that of other TRP channels, although the intracellular architecture is different. Interestingly, overlaying a TRPC4 monomer with representative TRP monomers from each TRP subfamily revealed that the overall fold of TRPC4 was closest to that of TRPM4 (Vinayagam et al, ). Conceivably, this insight into TRPC4 structures permits predictions about binding sites, which probably exist on the channel for modulators such as EA, TZL, and Pico145 and can preferably be supplemented by costructural data for ligands and the channel together.…”

Section: Future Directionsmentioning

confidence: 99%

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Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels

Rubaiy

2019

British J Pharmacology

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Canonical or classical transient receptor potential 4 and 5 proteins (TRPC4 and TRPC5) assemble as homomers or heteromerize with TRPC1 protein to form functional nonselective cationic channels with high calcium permeability. These channel complexes, TRPC1/4/5, are widely expressed in nervous and cardiovascular systems, also in other human tissues and cell types. It is debatable that TRPC1 protein is able to form a functional ion channel on its own. A recent explosion of molecular information about TRPC1/4/5 has emerged including knowledge of their distribution, function, and regulation suggesting these three members of the TRPC subfamily of TRP channels play crucial roles in human physiology and pathology. Therefore, these ion channels represent potential drug targets for cancer, epilepsy, anxiety, pain, and cardiac remodelling. In recent years, a number of highly selective small-molecule modulators of TRPC1/4/5 channels have been identified as being potent with improved pharmacological properties. This review will focus on recent remarkable small-molecule agonists: (−)-englerin A and tonantzitlolone and antagonists: Pico145 and HC7090, of TPRC1/4/5 channels. In addition, this work highlights other recently identified modulators of these channels such as the benzothiadiazine derivative, riluzole, ML204, clemizole, and AC1903. Together, these treasure troves of agonists and antagonists of TRPC1/4/5 channels provide valuable hints to comprehend the functional importance of these ion channels in native cells and in vivo animal models. Importantly, human diseases and disorders mediated by these proteins can be studied using these compounds to perhaps initiate drug discovery efforts to develop novel therapeutic agents.

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Section: Future Directionsmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

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Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels

Rubaiy

2019

British J Pharmacology

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“…Several high resolution TRPC structures have been determined by single-particle cryo-electron microscopy (cryo-EM), including zebrafish TRPC4, 32 mouse TRPC4, 33 and mouse TRPC5. 34 To date, TRPC6 is the only TRPC channel for which small molecule-bound structures have been reported.…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM structures of human TRPC5 reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site

Wright

Simmons

et al. 2020

Preprint

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TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered the first clinical trials. However, fundamental and translational studies require a better understanding of TRPC1/4/5 channel regulation by endogenous and exogenous factors. Although several potent and selective TRPC1/4/5 modulators have been reported, the paucity of mechanistic insights into their modes-of-action remains a barrier to the development of new chemical probes and drug candidates. The xanthine class of modulators includes the most potent and selective TRPC1/4/5 inhibitors described to date, as well as TRPC5 activators. Our previous studies suggest that xanthines interact with a, so far, elusive pocket of TRPC1/4/5 channels that is essential to channel gating. Targeting this pocket may be a promising strategy for TRPC1/4/5 drug discovery. Here we report the first structure of a small molecule-bound TRPC1/4/5 channelhuman TRPC5 in complex with the xanthine Pico145to 3.0 Å. We found that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a bound phospholipid. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn 2+ ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators.

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“…The regions with the largest structural divergences are the intracellular domains. While TRPV channels are almost structurally identical [3,[5][6][7][8][9][10][11] and share homology with TRPA1 [12], the TRPM and TRPC channels have amino and carboxy-termini with very different topology [13][14][15][16][17][18][19] (Figure 1). The thermoTRP channels are a subgroup of 11 members of the TRPA, TRPV, TRPC, and TRPM subfamilies.…”

Section: Introductionmentioning

confidence: 99%

What is new about mild temperature sensing? A review of recent findings

García-Ávila

Islas

2019

Temperature

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The superfamily of Transient Receptor Potential (TRP) channels is composed by a group of calcium-permeable ionic channels with a generally shared topology. The thermoTRP channels are a subgroup of 11 members, found in the TRPA, TRPV, TRPC, and TRPM subfamilies. Historically, members of this subgroup have been classified as cold, warm or hot-specific temperature sensors. Recently, new experimental results have shown that the role that has been given to the thermoTRPs in thermosensation is not necessarily strict. In addition, it has been shown that these channels activate over temperature ranges, which can have variations depending on the species and the interaction with a specific biological context. Investigation of these interactions could help to elucidate the mechanisms of activation by temperature, which remains uncertain.

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Electron cryo-microscopy structure of the canonical TRPC4 ion channel

Cited by 27 publications

References 72 publications

Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels

Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels

Cryo-EM structures of human TRPC5 reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site

What is new about mild temperature sensing? A review of recent findings

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