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The androgen receptor (AR) belongs to the steroid hormone group nuclear receptor family with the estrogen, progesterone, glucocorticoid and mineralcorticoid receptor.
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=== Cryo-EM Structure of the Human TRPV1 Ion Channel ===
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AR mediate the actions of testosterone (T) and a more biologically active form, 5α-dihydrotestosterone (DHT), which are the male sex hormones required for development of the male reproductive system and secondary sexual characteristics. This receptor, located on the X chromosome, is expressed in a diverse range of tissues, because they have significant biological actions in many systems <ref>PMID: 27057074</ref>. There are other androgens that bind with much less potency than T and DHT such as androstenedione, androstenediol, and dehydroepiandrosterone (DHEA) <ref>PMID: 36376977 </ref>.
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=Structure=
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<StructureSection
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Like members of the nuclear receptor family, the AR consists of three main functional domains which aid in controlling and regulating transcriptional activity.
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load='3j5p'
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==Domains==
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size='340'
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===N-terminal Domain (NTD)(residues 1-555)===
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side='right'
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This region is required for full transcriptional activity <ref>PMID: 24909511 </ref>, because of its necessary presence for LBD activation <ref>PMID: 33076388</ref>. It is the most variable domain, the sequence and lengths of the polyglutamine (CAG) and polyglycine (GGC) repeats are highly variable in the human population. It has been shown that the length of the polyglutamine repeat region affects the folding and structure of this domain, shorter repeats generally impose a higher AR transactivation activity, whereas longer repeats cause reduced activity <ref>PMID: 24909511 </ref>. In healthy people, one region of the AR gene shows up to 36 repeats of the CAG sequence. Patients with abnormally high numbers of CAG repeats can develop spinal muscular atrophy.
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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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===DNA-binding Domain (DBD) (residues 555-623)===
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scene=''>
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DBD is a cysteine-rich region that is the most highly conserved one of the steroid hormone nuclear receptor family <ref>PMID: 24909511 </ref>, but it has been shown that binding of selective androgen response elements (AREs) allow the specific activation functions of the AR. They facilitate direct DNA binding of the AR to the promoter and enhancer regions of AR-regulated genes, thereby allowing the activation functions of the N-terminal and ligand binding domains to stimulate or repress the transcription of these genes <ref>PMID: 27057074</ref>.
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</StructureSection>
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AR is a dimer, like other steroid receptors, that binds to promoter DNA response elements consisting of two equal, common hexameric half-sites, separated by a 3 base-pair spacer <ref>PMID: 24909511 </ref>'''IMAGEN DEL DÍMERO''', and this domain is critical for AR function, because it plays a role in dimerization and binding of dimerized AR to select motifs on target DNA <ref>PMID: 33076388</ref>.
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Each DBD monomer has a core composed of two zinc finger motifs, which consists of four cysteine residues that coordinate a zinc ion <ref>PMID: 24909511 </ref>. The first is closer to the NTD which has the P box, which is identical in all the family, and controls the DNA binding specificity at AREs, located in the regulatory regions of genes <ref>PMID: 33076388</ref>.
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The second zinc finger motif facilitates AR dimerization via the D box. Additionally, a nuclear localization signal (NLS) is localized at the junction between the DBD and the hinge region and it binds to importin-α and facilitates nuclear translocation <ref>PMID: 33076388</ref>. This is because passive transport across the nuclear pore complex has been suggested ranging from 20–40 kDa, in contrast, the AR, which is 110 kDa in size, requires help to be actively transported upon ligand binding <ref>PMID: 24909511 </ref>.
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The DBD is linked to the ligand binding domain by a flexible hinge region (residues 623-665), which is a linker poorly conserved. Once in the nucleus, this region also interacts with the DBD to identify specific sequences for AR binding. It controls the AR activation and degradation. Consequently, mutations in the hinge region can lead to enhanced AR potency <ref>PMID: 33076388</ref>.
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=== 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 ===
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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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<StructureSection load='3b5r' size='350' side='right' caption='AR' scene=''>
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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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<scene name='85/857155/H12_androgen_receptor/1'>H12</scene>
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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.
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<scene name='85/857155/Bicatulamide_in_ar/1'>bicatulamide</scene>
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</StructureSection>
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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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