TRPV1 pore turret dictates distinct DkTx and capsaicin gating

Geron, Matan; Kumar, Rakesh; Zhou, Wenchang; Faraldo‐Gómez, José D.; Vásquez, Valeria; Priel, Avi

doi:10.1073/pnas.1809662115

Cited by 46 publications

(53 citation statements)

References 64 publications

(133 reference statements)

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“…The value is slightly lower than that estimated from current recordings, an observation resembling that for capsaicin (Figure S1). Similar observations were previously reported and attributed to differences in the two detection methods (Geron et al, ). Importantly, the T551V mutation shifted the concentration–response curve substantially to the right, increasing the EC 50 value to 3.9 ± 0.5 μM ( n = 6).…”

Section: Resultssupporting

confidence: 91%

Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers

Yin

Dong

et al. 2019

British J Pharmacology

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Background and Purpose Like chili peppers, gingers produce pungent stimuli by a group of vanilloid compounds that activate the nociceptive transient receptor potential vanilloid 1 (TRPV1) ion channel. How these compounds interact with TRPV1 remains unclear. Experimental Approach We used computational structural modelling, functional tests (electrophysiology and calcium imaging), and mutagenesis to investigate the structural mechanisms underlying ligand–channel interactions. Key Results The potency of three principal pungent compounds from ginger —shogaol, gingerol, and zingerone—depends on the same two residues in the TRPV1 channel that form a hydrogen bond with the chili pepper pungent compound, capsaicin. Computational modelling revealed binding poses of these ginger compounds similar to those of capsaicin, including a “head‐down tail‐up” orientation, two specific hydrogen bonds, and important contributions of van der Waals interactions by the aliphatic tail. Our study also identified a novel horizontal binding pose of zingerone that allows it to directly interact with the channel pore when bound inside the ligand‐binding pocket. These observations offer a molecular level explanation for how unique structures in the ginger compounds affect their channel activation potency. Conclusions and Implications Mechanistic insights into the interactions of ginger compounds and the TRPV1 cation channel should help guide drug discovery efforts to modulate nociception.

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Section: Resultssupporting

confidence: 91%

Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers

Yin

Dong

et al. 2019

British J Pharmacology

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“…As for changes in the conductance of TRPV1 due to the actions of agonists, it is interesting to note that, it has been recently reported that DkTx diminishes the unitary conductance by 32% of TRPV1, as compared to that observed with capsaicin [159]. DkTx is a molecule composed of two moieties joined by a short linker, which bind in the outer pore region of the channel so that each motif sits at a subunit interface [45].…”

Section: Discussionmentioning

confidence: 99%

TRP ion channels: Proteins with conformational flexibility

et al. 2019

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Ion channels display conformational changes in response to binding of their agonists and antagonists. The study of the relationships between the structure and the function of these proteins has witnessed considerable advances in the last two decades using a combination of techniques, which include electrophysiology, optical approaches (i.e. patch clamp fluorometry, incorporation of non-canonic amino acids, etc.), molecular biology (mutations in different regions of ion channels to determine their role in function) and those that have permitted the resolution of their structures in detail (X-ray crystallography and cryo-electron microscopy). The possibility of making correlations among structural components and functional traits in ion channels has allowed for more refined conclusions on how these proteins work at the molecular level. With the cloning and description of the family of Transient Receptor Potential (TRP) channels, our understanding of several sensory-related processes has also greatly moved forward. The response of these proteins to several agonists, their regulation by signaling pathways as well as by protein-protein and lipid-protein interactions and, in some cases, their biophysical characteristics have been studied thoroughly and, recently, with the resolution of their structures, the field has experienced a new boom. This review article focuses on the conformational changes in the pores, concentrating on some members of the TRP family of ion channels (TRPV and TRPA subfamilies) that result in changes in their single-channel conductances, a phenomenon that may lead to fine-tuning the electrical response to a given agonist in a cell.

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“…In a TRPV2 channel engineered to be sensitive to RTX, an even more drastic dilation of the upper gate was recently observed as the channel transitions from fourfold to twofold symmetry upon binding RTX (Zubcevic et al, 2018b), further confirming the existence of an upper gate within the TRPV channels. Such flexibility within the TRPV1 outer pore region also likely contributes to distinct single-channel conductance states evoked by different TRPV1 agonists (Canul-Sánchez et al, 2018; Geron et al, 2018).…”

Section: The “Resolution Revolution” Led To Breakthrough In Trpv1 Structural Biologymentioning

confidence: 99%

Structural mechanisms of transient receptor potential ion channels

Cao

2020

Journal of General Physiology

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Transient receptor potential (TRP) ion channels are evolutionarily ancient sensory proteins that detect and integrate a wide range of physical and chemical stimuli. TRP channels are fundamental for numerous biological processes and are therefore associated with a multitude of inherited and acquired human disorders. In contrast to many other major ion channel families, high-resolution structures of TRP channels were not available before 2013. Remarkably, however, the subsequent “resolution revolution” in cryo-EM has led to an explosion of TRP structures in the last few years. These structures have confirmed that TRP channels assemble as tetramers and resemble voltage-gated ion channels in their overall architecture. But beyond the relatively conserved transmembrane core embedded within the lipid bilayer, each TRP subtype appears to be endowed with a unique set of soluble domains that may confer diverse regulatory mechanisms. Importantly, TRP channel structures have revealed sites and mechanisms of action of numerous synthetic and natural compounds, as well as those for endogenous ligands such as lipids, Ca2+, and calmodulin. Here, I discuss these recent findings with a particular focus on the conserved transmembrane region and how these structures may help to rationally target this important class of ion channels for the treatment of numerous human conditions.

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TRPV1 pore turret dictates distinct DkTx and capsaicin gating

Cited by 46 publications

References 64 publications

Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers

Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers

TRP ion channels: Proteins with conformational flexibility

Structural mechanisms of transient receptor potential ion channels

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