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<span style="font-size:160%"><b>Structural basis for regulation of rhizobial nodulation
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=== Cryo-EM Structure of the Human TRPV1 Ion Channel ===
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and symbiosis gene expression by the regulatory
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protein NolR.</b></span>
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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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<span style="font-size:100%">
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=== Introduction ===
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Soon Goo Lee, Hari B.Krishnan and Joseph M.Jez
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[https://doi.org/10.1073/pnas.1402243111] (2014).
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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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[https://doi.org/10.1073/pnas.1402243111]
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</span>
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</td></tr></table>
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__NOTOC__
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==Structure Tour==
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<StructureSection size='[250,500]' side='right' caption='' scene='83/834714/Filament/7'>
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===Background===
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Previously, pili of ''Geobacter sulfurreducens'' were thought to be composed of PilA-N, a 61-amino acid protein<ref name="blindmen">PMID: 33070100</ref><ref name="homolmod">PMID: 25736881 </ref><ref name="lovleyreview">PMID: 31608018 </ref>. Immediately downstream from the ''pilA-N'' gene is ''pilA-C'', coding for a 104 amino acid protein suspected to be the missing C-terminal globular domain of PilA-N<ref>PMID:22408162 </ref><ref>PMID:28348867</ref>. Gene fission of pilins is widely distributed in ''Desulfuromonadales'' including ''Geobacteracae''<ref>PMID: 28066394</ref>. In addition to pili, electrically conductive nanowires composed of linear polymers of cytochromes OmcS and OmcZ have been reported<ref name="nw1">PMID: 30951668</ref><ref name="nw2">PMID: 31925024</ref><ref name="omcz">PMID: 32807967</ref>.
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===Pilus Structure===
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=== Structural Highlights ===
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{{Template:ClickGreenLinks}}
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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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Our electron cryomicroscopic structure of ''Geobacter sulfurreducens'' pili (<scene name='83/834714/Filament/7'>restore initial scene</scene>), [[6vk9]], reveals them to be <scene name='83/834714/Filament/9'>composed of a core</scene> of '''<font color='#e87000'>PilA-N</font>''' (61 amino acids) coated with an outer surface layer of '''<font color='00a0a0'>PilA-C</font>''' (104 amino acids). Here is a <scene name='83/834714/Filament/10'>cutaway view</scene> (front half hidden). The C-termini of '''<font color='#e87000'>PilA-N</font>''' <scene name='83/834714/Filament/3'>protrude into sockets</scene> in '''<font color='00a0a0'>PilA-C</font>'''.
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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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The '''PilA-N''' subunits have extensive hydrophobic contacts with each other, stabilizing the hydrophobic core of the filament. <scene name='83/834714/Filament/11'>View PilA-N with PilA-C hidden</scene>. Each PilA-N chain contacts 75 carbon atoms from 11 adjacent PilA-N chains, and also has 4 hydrogen bonds and 4 salt bridges with adjacent PilA-N chains (not shown). In contrast, '''PilA-C''' subunits (<scene name='83/834714/Filament/12'>view PilA-C with front half and PilA-N hidden</scene>) have little contact with each other: 14 atoms, which are mostly hydrogen bonded, with one salt bridge (not shown).
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===Heterodimers===
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The pilus filament is assembled from <scene name='83/834714/Dimer/5'>heterodimers</scene>. Dimer <scene name='83/834714/Dimer/6'>secondary structure</scene>: '''<font color='#e87000'>PilA-N</font>''' consists of two alpha helices, while '''<font color='00a0a0'>PilA-C</font>''' includes a 3-stranded beta sheet. The C-terminal protrusion of '''<font color='#e87000'>PilA-N</font>''' is <scene name='83/834714/Flaps/7'>held between two flaps</scene> (darker) of '''<font color='00a0a0'>PilA-C</font>'''. The flaps have almost no contact with each other. They are held in place by apolar contacts and hydrogen bonds with the C-terminal protrusion of '''<font color='#e87000'>PilA-N</font>'''. These flaps might be open before '''<font color='#e87000'>PilA-N</font>''' arrives to form a dimer, reminiscent of the flaps of HIV protease<ref>PMID: 16418268</ref>. (See, for example, [[1hxw]] and [[Flaps Morph for HIV Protease]].) <scene name='83/834714/Flaps/8'>Four glycines</scene> (<font color="red">'''red: 10, 11, 31, 37'''</font>) provide flexibility that could enable opening of the flaps.
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===Other Findings and Conclusions===
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As detailed in the journal publication, the PilA-N-C pili studied here are 20-fold less electrically conductive than the nanowires composed of OmcS cytochromes<ref name="nw1" /><ref name="nw2" />, and 20,000-fold less conductive than OmcZ nanowires<ref name="omcz" />. These PilA-N-C pili lack the structural hallmarks of type 4 pili, but share structural characteristics with pseudopili. PilA-N and PilA-C remain in the inner membrane, unless the gene for OmcS (or OmcZ) is deleted, in which case they form the pili extending outside the cell studied here. When the ''pilA-N'' gene is deleted, OmcS nanowires fail to be produced. It is proposed in the journal publication that PilA-N-C is part of a secretion system required for production of OmcS/OmcZ nanowires.
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</StructureSection>
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<br>
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=== Significance ===
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<hr><br>
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==See Also==
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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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* [[6vk9]], the structure described here.
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* [[Malvankar]]: A list of all interactive 3D complements for publications from the Malvankar group, including:
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** Structure of the OmcS conductive nanowire: [[Malvankar/2|2019, Cell: Structure of Microbial Nanowires Reveals Stacked Hemes that Transport Electrons over Micrometers.]]
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==Notes & References==
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=== References ===
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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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