Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM

Hughes, Taylor; Lodowski, David T.; Huynh, Kevin W.; Yazici, Aysenur; Rosario, Del; Kapoor, Anoop; Basak, Sandip; Samanta, Amrita; Xu, Han; Chakrapani, Sudha; Zhou, Z. Hong; Filizola, Marta; Rohács, Tibor; Han, Seungil; Moiseenkova-Bell, Vera Y.

doi:10.1038/s41594-017-0009-1

Cited by 119 publications

(157 citation statements)

References 60 publications

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“…This signature is composed of three amino acids located at the N-terminal helix-loophelix (HLH) domain in mammals and sauropsids ( Figure 4a). According to recently published structures (Hughes et al, 2018a;Singh et al, 2017), the HLH domain sits close to the S2-S3 intracellular linker and conveniently adjacent to the TRP domain helix (TD-helix), a known modulator of TRP channel gating (Gregorio-teruel et al, 2015;Valente et al, 2008) (Figure 4b).…”

Section: Fast Inactivation Is a Functional Property Associated To Thementioning

confidence: 99%

Evolutionary analyses unveil the molecular mechanism of fast inactivation in calcium-permeable TRP channels

Flores-Aldama

Zavala

et al. 2019

Preprint

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Important for calcium homeostasis, TRPV5 and TRPV6 are calcium-selective channels belonging to the transient receptor potential (TRP) gene family. In this study, we investigated the evolutionary history of these channels to add an evolutionary context to the already available physiological information. Phylogenetic analyses revealed that paralogs found in mammals, sauropsids, amphibians, and chondrichthyans, are the product of independent duplication events in the ancestor of each group. Within amniotes, we identified a traceable signature of three amino acids located at the amino-terminal intracellular region (HLH domain). The signature correlates well with both the duplication events and the phenotype of fast inactivation observed in mammalian TRPV6 channels. Electrophysiological recordings and mutagenesis suggest that calcium-induced fast inactivation represents an evolutionary innovation that emerged independently after gene duplication.

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Section: Fast Inactivation Is a Functional Property Associated To Thementioning

confidence: 99%

Evolutionary analyses unveil the molecular mechanism of fast inactivation in calcium-permeable TRP channels

Flores-Aldama

Zavala

et al. 2019

Preprint

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“…The TRPV channel subfamily members (TRPV1-TRPV6) have strong structural homology 13 , yet the effects of lipids on these channels are widely divergent [14][15][16][17][18] . Structural studies of members of this family have shown that both modulating and structural lipids can bind the "vanilloid" pocket located in the transmembrane domain (TMD) between the S3 and S4 helices and the helical S4-S5 linker of each monomer [15][16][17] . This pocket has also been shown to be a drug binding site in some TRPV channels and different occupants of this pocket can transmit conformational changes into the pore which affect gating 15,16 .…”

Section: Introductionmentioning

confidence: 99%

“…Structural studies of members of this family have shown that both modulating and structural lipids can bind the "vanilloid" pocket located in the transmembrane domain (TMD) between the S3 and S4 helices and the helical S4-S5 linker of each monomer [15][16][17] . This pocket has also been shown to be a drug binding site in some TRPV channels and different occupants of this pocket can transmit conformational changes into the pore which affect gating 15,16 . This "vanilloid" pocket does not have very strong lipid density in currently available structures of TRPV2 [18][19][20] , TRPV3 21,22 and TRPV4 23 channels, while annular or modulating lipids have strong density in this pocket in TRPV1 15 , TRPV5 16 and TRPV6 17 channels.…”

Section: Introductionmentioning

confidence: 99%

“…This pocket has also been shown to be a drug binding site in some TRPV channels and different occupants of this pocket can transmit conformational changes into the pore which affect gating 15,16 . This "vanilloid" pocket does not have very strong lipid density in currently available structures of TRPV2 [18][19][20] , TRPV3 21,22 and TRPV4 23 channels, while annular or modulating lipids have strong density in this pocket in TRPV1 15 , TRPV5 16 and TRPV6 17 channels. One lipid of interest for this study is phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), which is a known modulator of all TRPV channels 14 , but it is uncertain whether the mechanisms of modulation are conserved among these closely related channels 14 .…”

Section: Introductionmentioning

confidence: 99%

“…PI(4,5)P2 has been shown to both activate 24 and inhibit TRPV2 18 , but the exact molecular mechanism is poorly understood 14 . On the other hand, the PI(4,5)P2 activation mechanism of TRPV5 and TRPV6 is conserved 25 and a novel PI(4,5)P2 binding site has recently been revealed using cryo-EM 16 .…”

Section: Introductionmentioning

confidence: 99%

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Molecular mechanism of TRPV2 channel modulation by cannabidiol

Pumroy

Samanta

Liu

et al. 2019

Preprint

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Transient receptor potential vanilloid 2 (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ingredient of Cannabis sativa, is a potent activator of TRPV2 and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length TRPV2 channel in a CBD-bound state in detergent and in PI(4,5)P2 enriched nanodiscs by cryo-electron microscopy. CBD interacts with TRPV2 through a hydrophobic pocket located between S5 and S6 helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. Comparison between apo-and two CBD-bound TRPV2 structures reveals that the S4-S5 linker plays a critical role in channel gating upon CBD binding. The TRPV2 "vanilloid" pocket, which is critical for ligand-dependent gating in other TRPV channels, stays unoccupied by annular lipids, PI(4,5)P2, or CBD. Together these results provide a foundation to further understand TRPV channel gating properties and their divergent physiological functions and to accelerate structure-based drug design.

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Multidisciplinary Advances Address the Challenges in Developing Drugs against Transient Receptor Potential Channels to Treat Metabolic Disorders

Wang

2023

ChemMedChem

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Transient receptor potential (TRP) channels are cation channels that regulate key physiological and pathological processes in response to a broad range of stimuli. Moreover, they systemically regulate the release of hormones, metabolic homeostasis, and complications of diabetes, which positions them as promising therapeutic targets to combat metabolic disorders. Nevertheless, there are significant challenges in the design of TRP ligands with high potency and durability. Herein we summarize the four challenges as hydrophobicity, selectivity, mono‐target therapy, and interspecies discrepancy. We present 1134 TRP ligands with diversified modes of TRP‐ligand interaction and provide a detailed discussion of the latest strategies, especially cryogenic electron microscopy (cryo‐EM) and computational methods. We propose solutions to address the challenges with a critical analysis of advances in membrane partitioning, polypharmacology, biased agonism, and biochemical screening of transcriptional modulators. They are fueled by the breakthrough from cryo‐EM, chemoinformatics and bioinformatics. The discussion is aimed to shed new light on designing next‐generation drugs to treat obesity, diabetes and its complications, with optimal hydrophobicity, higher mode selectivity, multi‐targeting and consistent activities between human and rodents.

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Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM

Cited by 119 publications

References 60 publications

Evolutionary analyses unveil the molecular mechanism of fast inactivation in calcium-permeable TRP channels

Evolutionary analyses unveil the molecular mechanism of fast inactivation in calcium-permeable TRP channels

Molecular mechanism of TRPV2 channel modulation by cannabidiol

Multidisciplinary Advances Address the Challenges in Developing Drugs against Transient Receptor Potential Channels to Treat Metabolic Disorders

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