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== NolR ==
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=== Cryo-EM Structure of the Human TRPV1 Ion Channel ===
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The symbiosis between rhizobial microbes and legume plants is fundamental to sustainable agriculture and ecological nitrogen cycling. This partnership requires coordinated expression of multiple genes to establish nitrogen-fixing nodules, with **NolR serving as a global transcriptional regulator** controlling this critical developmental process across diverse *Rhizobium* species.
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<StructureSection
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load='3j5p'
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size='340'
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side='right'
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caption='Cryo-EM structure of the human TRPV1 ion channel in the apo state (Liao et al., 2013; ~3.5 Å resolution)'
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scene=''>
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</StructureSection>
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We present the first high-resolution X-ray crystal structures of NolR in both unliganded and DNA-bound forms, revealing its complex interactions with asymmetric operator sequences. Analysis of NolR complexed with two different 22-base pair operator DNA sequences (oligos AT and AA) demonstrates that this **homodimeric transcription factor adopts a winged helix-turn-helix fold** and recognizes DNA through a combination of positively charged surface residues that engage the DNA phosphate backbone and specific base contacts.
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=== Introduction ===
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The most striking finding is a **conformational switching mechanism involving Gln56**, which alters its position to accommodate variation in target DNA sequences without changing overall binding affinity. This elegant mechanism allows NolR to regulate multiple nodulation and symbiosis genes with different operator sequences through modulation of thermodynamic binding contributions. The conformational flexibility of this key residue represents a novel regulatory strategy in the ArsR/SmtB transcription factor family.
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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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These structural studies provide unprecedented molecular insight into **how NolR functions as a global regulatory hub**, proposing two distinct regulatory models for differential gene expression during nodule formation and symbiotic nitrogen fixation. This work illuminates the structural basis for one of nature's most important agricultural and ecological partnerships.
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=== Structural Highlights ===
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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 ===
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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 ===
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* Liao M., Cao E., Julius D., Cheng Y. (2013). Structure of the TRPV1 ion channel determined by electron cryo-microscopy. *Nature*, 504, 107–112.

Current revision

Contents

Cryo-EM Structure of the Human TRPV1 Ion Channel

Cryo-EM structure of the human TRPV1 ion channel in the apo state (Liao et al., 2013; ~3.5 Å resolution)

Drag the structure with the mouse to rotate

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.
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