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| - | + | === Cryo-EM Structure of the Human TRPV1 Ion Channel === | |
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| - | < | + | <StructureSection |
| - | </ | + | load='3j5p' |
| + | size='340' | ||
| + | side='right' | ||
| + | caption='Cryo-EM structure of the human TRPV1 ion channel in the apo state (Liao et al., 2013; ~3.5 Å resolution)' | ||
| + | scene=''> | ||
| + | </StructureSection> | ||
| - | + | === Introduction === | |
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| - | + | The transient receptor potential vanilloid 1 (TRPV1) ion channel is a heat- and ligand-gated cation channel essential for nociception, inflammatory pain, and thermal sensitivity. Activated by capsaicin, protons, noxious heat (>42°C), and lipid mediators, TRPV1 serves as a polymodal molecular sensor in the peripheral nervous system. Because of its central role in pain signaling, TRPV1 has been a major therapeutic target for developing next-generation analgesics. Understanding its three-dimensional structure is therefore crucial for elucidating its gating mechanism and ligand recognition. | |
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| - | == | + | === Structural Highlights === |
| - | + | Using single-particle cryo-electron microscopy, Liao, Cao, Julius, and Cheng (2013) determined the first near-atomic structures of TRPV1 in multiple functional states, including the apo (resting), capsaicin-bound, and toxin-bound conformations. TRPV1 assembles as a homotetramer, with each subunit containing six transmembrane helices (S1–S6), a re-entrant pore loop, and extensive cytosolic ankyrin repeat domains. | |
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| - | + | The vanilloid-binding pocket—formed between the S3–S4 helices and the S4–S5 linker—was resolved in detail, explaining how capsaicin stabilizes the open conformation by pulling on the S4–S5 linker and reshaping the S6 helices to widen the pore. Structures bound to the double-knot toxin (DkTx) reveal an even more dilated pore, representing a fully activated gating state. Comparisons across these states demonstrate the sequence of conformational rearrangements that underlie heat and ligand gating in TRPV1. | |
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| - | + | === Significance === | |
| - | + | These cryo-EM structures provide a mechanistic blueprint for understanding how TRPV1 integrates thermal, chemical, and lipid-derived signals to regulate ion permeation. They reveal conserved gating transitions and define pharmacologically relevant ligand-binding pockets essential for rational drug design. The ability to visualize TRPV1 in distinct activation states enables development of selective analgesic modulators targeting neuropathic and inflammatory pain while minimizing adverse thermo-sensory effects. | |
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| - | === | + | === References === |
| - | + | * Liao M., Cao E., Julius D., Cheng Y. (2013). Structure of the TRPV1 ion channel determined by electron cryo-microscopy. *Nature*, 504, 107–112. | |
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Current revision
Contents |
Cryo-EM Structure of the Human TRPV1 Ion Channel
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Introduction
The transient receptor potential vanilloid 1 (TRPV1) ion channel is a heat- and ligand-gated cation channel essential for nociception, inflammatory pain, and thermal sensitivity. Activated by capsaicin, protons, noxious heat (>42°C), and lipid mediators, TRPV1 serves as a polymodal molecular sensor in the peripheral nervous system. Because of its central role in pain signaling, TRPV1 has been a major therapeutic target for developing next-generation analgesics. Understanding its three-dimensional structure is therefore crucial for elucidating its gating mechanism and ligand recognition.
Structural Highlights
Using single-particle cryo-electron microscopy, Liao, Cao, Julius, and Cheng (2013) determined the first near-atomic structures of TRPV1 in multiple functional states, including the apo (resting), capsaicin-bound, and toxin-bound conformations. TRPV1 assembles as a homotetramer, with each subunit containing six transmembrane helices (S1–S6), a re-entrant pore loop, and extensive cytosolic ankyrin repeat domains.
The vanilloid-binding pocket—formed between the S3–S4 helices and the S4–S5 linker—was resolved in detail, explaining how capsaicin stabilizes the open conformation by pulling on the S4–S5 linker and reshaping the S6 helices to widen the pore. Structures bound to the double-knot toxin (DkTx) reveal an even more dilated pore, representing a fully activated gating state. Comparisons across these states demonstrate the sequence of conformational rearrangements that underlie heat and ligand gating in TRPV1.
Significance
These cryo-EM structures provide a mechanistic blueprint for understanding how TRPV1 integrates thermal, chemical, and lipid-derived signals to regulate ion permeation. They reveal conserved gating transitions and define pharmacologically relevant ligand-binding pockets essential for rational drug design. The ability to visualize TRPV1 in distinct activation states enables development of selective analgesic modulators targeting neuropathic and inflammatory pain while minimizing adverse thermo-sensory effects.
References
- Liao M., Cao E., Julius D., Cheng Y. (2013). Structure of the TRPV1 ion channel determined by electron cryo-microscopy. *Nature*, 504, 107–112.
