Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands

Su, Nannan; Zhen, Wenxuan; Zhang, Heng; Xu, Li; Jin, Yitian; Chen, Xiaoying; Zhao, Cheng; Wang, Qinrui; Wang, Xinyan; Li, Shaowei; Wen, Han; Yang, Wei; Guo, Jiangtao; Yang, Fan

doi:10.1038/s41589-022-01139-8

Cited by 20 publications

(21 citation statements)

References 58 publications

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“…This indicates that the lipid of TRPV2 C16-1 has been replaced, and we have instead tentatively assigned a cholesteryl hemisuccinate (CHS) at this location in TRPV2 C16-2 , based on the shape of the feature. CHS is included in the protein preparation and could mimic native cholesterol, and is also in agreement with the equivalent binding of cholesterol to a previous structure of TRPV2 30 (PDB-ID: 7XEM) and CHS to TRPV6 58 (PDB-ID: 7S89) (Supplementary Fig. 12).…”

Section: C16 Effects On the Vanilloid Pocket Regionsupporting

confidence: 55%

“…To date, the effects of RTX, CBD, PLG, and 2-APB on TRPV2 structurefunction have been studied using cryo-EM or X-ray crystallography 27,28,30,44,45 (Supplementary Fig. 8a, b).…”

Section: Cryo-em Structures Of Trpv2 In the Presence Of C16mentioning

confidence: 99%

“…The first high-resolution structures of TRPV1 22 using cryo-EM paved the way for understanding how polymodal TRP channels are gated at a near atom level, and many cryo-EM structures of TRPV channels, including TRPV2, are now available 21,[23][24][25] . Importantly, recent cryo-EM studies of TRPV2 have proposed ligand binding sites for both activators such as cannabidiol (CBD), resiniferatoxin (RTX), and 2-APB as well as the inhibitor piperlongumine (PLG) [26][27][28][29][30] .…”

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confidence: 99%

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Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function

et al. 2022

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TRPV2 is a ligand-operated temperature sensor with poorly defined pharmacology. Here, we combine calcium imaging and patch-clamp electrophysiology with cryo-electron microscopy (cryo-EM) to explore how TRPV2 activity is modulated by the phytocannabinoid Δ9-tetrahydrocannabiorcol (C16) and by probenecid. C16 and probenecid act in concert to stimulate TRPV2 responses including histamine release from rat and human mast cells. Each ligand causes distinct conformational changes in TRPV2 as revealed by cryo-EM. Although the binding for probenecid remains elusive, C16 associates within the vanilloid pocket. As such, the C16 binding location is distinct from that of cannabidiol, partially overlapping with the binding site of the TRPV2 inhibitor piperlongumine. Taken together, we discover a new cannabinoid binding site in TRPV2 that is under the influence of allosteric control by probenecid. This molecular insight into ligand modulation enhances our understanding of TRPV2 in normal and pathophysiology.

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Section: C16 Effects On the Vanilloid Pocket Regionsupporting

confidence: 55%

“…To date, the effects of RTX, CBD, PLG, and 2-APB on TRPV2 structurefunction have been studied using cryo-EM or X-ray crystallography 27,28,30,44,45 (Supplementary Fig. 8a, b).…”

Section: Cryo-em Structures Of Trpv2 In the Presence Of C16mentioning

confidence: 99%

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confidence: 99%

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Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function

et al. 2022

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“…Additionally, an increasing number of studies identify TRPV2 as an important biomarker 29–31 and a potential therapeutic target for multiple types of cancers, 32 controlling pathways of cell survival, migration, proliferation, and invasion signaling. Recent cryo‐EM structures revealed the interaction between TRPV2 and the lipid environment, its known activators 2‐APB and cannabidiol (CBD), and an inhibitor piperlongumine 16,18,33,34 . As cryo‐EM is currently limited to snapshots frozen in time, molecular dynamics simulation is a critical tool for examining the complex and transient interactions between proteins, lipids, and ligands.…”

Section: Introductionmentioning

confidence: 99%

“…Recent cryo-EM structures revealed the interaction between TRPV2 and the lipid environment, its known activators 2-APB and cannabidiol (CBD), and an inhibitor piperlongumine. 16,18,33,34 As cryo-EM is currently limited to snapshots frozen in time, molecular dynamics simulation is a critical tool for examining the complex and transient interactions between proteins, lipids, and ligands.…”

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confidence: 99%

Modulation of TRPV2 by endogenous and exogenous ligands: A computational study

et al. 2022

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Transient receptor potential vanilloid (TRPV) channels play various important roles in human physiology. As membrane proteins, these channels are modulated by their endogenous lipid environment as the recent wealth of structural studies has revealed functional and structural lipid binding sites. Additionally, it has been shown that exogenous ligands can exchange with some of these lipids to alter channel gating. Here, we used molecular dynamics simulations to examine how one member of the TRPV family, TRPV2, interacts with endogenous lipids and the pharmacological modulator cannabidiol (CBD). By computationally reconstituting TRPV2 into a typical plasma membrane environment, which includes phospholipids, cholesterol, and phosphatidylinositol (PIP) in the inner leaflet, we showed that most of the interacting surface lipids are phospholipids without strong specificity for headgroup types. Intriguingly, we observed that the C-terminal membrane proximal region of the channel binds preferentially to PIP lipids. We also modelled two structural lipids in the simulation: one in the vanilloid pocket and the other in the voltage sensor-like domain (VSLD) pocket. The simulation shows that the VSLD lipid dampens the fluctuation of the VSLD residues, while the vanilloid lipid exhibits heterogeneity both in its binding pose and in its influence on protein dynamics.Addition of CBD to our simulation system led to an open selectivity filter and a structural rearrangement that includes a clockwise rotation of the ankyrin repeat domains, TRP helix, and VSLD. Together, these results reveal the interplay between endogenous lipids and an exogenous ligand and their effect on TRPV2 stability and channel gating.

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Is deep brain imaging on the brink of transformation with a bioluminescence molecule?

Xu,

Manshaii,

Chen

2024

BMEMat

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Cephalofurimazine (CFz), when paired with Antares luciferase, shows superior blood‐brain barrier permeability and enhanced imaging depth and clarity for deep brain imaging. This bioluminescence provides a less invasive method for real‐time monitoring of deep brain activity, with the potential to advance targeted therapies and deepen our understanding of brain functions. Further molecular engineering and localized delivery can reduce the potential toxicity of CFz and enhance its efficacy for clinical deep brain imaging.

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Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands

Cited by 20 publications

References 58 publications

Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function

Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function

Modulation of TRPV2 by endogenous and exogenous ligands: A computational study

Is deep brain imaging on the brink of transformation with a bioluminescence molecule?

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