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- PDB-9w4m: ratTRPV1 bound with antagonist AMG517 -

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Entry
Database: PDB / ID: 9w4m
TitleratTRPV1 bound with antagonist AMG517
ComponentsMaltose/maltodextrin-binding periplasmic protein,Transient receptor potential cation channel subfamily V member 1
KeywordsMEMBRANE PROTEIN / antagonist / complex
Function / homology
Function and homology information


negative regulation of iodide transmembrane transport / negative regulation of establishment of blood-brain barrier / peptide secretion / sensory perception of mechanical stimulus / detection of temperature stimulus involved in thermoception / positive regulation of membrane depolarization / positive regulation of renal sodium excretion / response to capsazepine / cellular response to temperature stimulus / detection of chemical stimulus involved in sensory perception of pain ...negative regulation of iodide transmembrane transport / negative regulation of establishment of blood-brain barrier / peptide secretion / sensory perception of mechanical stimulus / detection of temperature stimulus involved in thermoception / positive regulation of membrane depolarization / positive regulation of renal sodium excretion / response to capsazepine / cellular response to temperature stimulus / detection of chemical stimulus involved in sensory perception of pain / positive regulation of sensory perception of pain / temperature-gated ion channel activity / smooth muscle contraction involved in micturition / TRP channels / fever generation / negative regulation of axon regeneration / diet induced thermogenesis / positive regulation of cardiac muscle cell differentiation / urinary bladder smooth muscle contraction / thermoception / response to pH / glutamate secretion / monoatomic cation transmembrane transporter activity / response to acidic pH / negative regulation of systemic arterial blood pressure / response to pain / excitatory extracellular ligand-gated monoatomic ion channel activity / dendritic spine membrane / positive regulation of urine volume / negative regulation of heart rate / cellular response to alkaloid / cellular response to cytokine stimulus / detection of maltose stimulus / sensory perception of taste / temperature homeostasis / maltose transport complex / intracellularly gated calcium channel activity / cellular response to ATP / negative regulation of mitochondrial membrane potential / detection of temperature stimulus involved in sensory perception of pain / carbohydrate transport / behavioral response to pain / calcium ion import across plasma membrane / positive regulation of vasoconstriction / carbohydrate transmembrane transporter activity / monoatomic ion channel activity / maltose binding / maltose transport / ligand-gated monoatomic ion channel activity / maltodextrin transmembrane transport / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / monoatomic cation channel activity / cellular response to acidic pH / extracellular ligand-gated monoatomic ion channel activity / ATP-binding cassette (ABC) transporter complex / sensory perception of pain / phosphatidylinositol binding / axon terminus / positive regulation of excitatory postsynaptic potential / lipid metabolic process / sarcoplasmic reticulum / cell chemotaxis / microglial cell activation / phosphoprotein binding / cellular response to tumor necrosis factor / cellular response to nerve growth factor stimulus / cellular response to growth factor stimulus / response to peptide hormone / GABA-ergic synapse / calcium ion transmembrane transport / calcium channel activity / positive regulation of nitric oxide biosynthetic process / calcium ion transport / transmembrane signaling receptor activity / cellular response to heat / outer membrane-bounded periplasmic space / response to heat / positive regulation of cytosolic calcium ion concentration / monoatomic ion transmembrane transport / protein homotetramerization / calmodulin binding / periplasmic space / postsynaptic membrane / neuron projection / positive regulation of apoptotic process / external side of plasma membrane / neuronal cell body / DNA damage response / dendrite / negative regulation of transcription by RNA polymerase II / ATP binding / membrane / metal ion binding / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / Ankyrin repeat / Ankyrin repeat profile. / Ankyrin repeats (3 copies) ...Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / Ankyrin repeat / Ankyrin repeat profile. / Ankyrin repeats (3 copies) / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
: / Transient receptor potential cation channel subfamily V member 1 / Maltose/maltodextrin-binding periplasmic protein
Similarity search - Component
Biological speciesEscherichia coli K-12 (bacteria)
Rattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsGao, Y.H. / Li, Z.X.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2021ZD0203400 China
CitationJournal: Cell Rep / Year: 2026
Title: Structures of TRPV1 bound by hyperthermia-inducing analgesics.
Authors: Yu-Hao Gao / Yi-Zhe Huang / Zhao-Xing Li / Xiao-Ying Chen / Chang-Yan Shao / Han-Wen Li / Bin Liu / Fán Yang / Mei-Rong Chen / Mei-Ling Lu / Michael X Zhu / Fan Yang / Yi-Bei Xiao / Ye Yu /
Abstract: TRPV1, a member of the transient receptor potential vanilloid subfamily, mediates nociception and thermoregulation. TRPV1-targeting analgesics frequently induce hyperthermia, underscoring the need ...TRPV1, a member of the transient receptor potential vanilloid subfamily, mediates nociception and thermoregulation. TRPV1-targeting analgesics frequently induce hyperthermia, underscoring the need for structural insights to guide the development of safer compounds. Here, we determined the structures of rat TRPV1 bound to the clinical candidate analgesics AMG517, AMG9810, and SB366791. AMG517 and AMG9810 are deeply situated within the S3-S4 interface of the vanilloid pocket, where they interact with residues from the S3-S6 helices, as well as the S4-S5 linker. These interactions induce local deformations in the TRP-box and lower S6 helix, accompanied by a modest rotation of the S1-S4 bundle, leading to partial dilation of the lower gate. The distinct allosteric changes of AMG517 and AMG9810, compared with the non-hyperthermic ligand SB366791, suggest a structural basis by which TRPV1-targeting analgesics influence thermoregulation and provide insights for designing safer analogs.
History
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,Transient receptor potential cation channel subfamily V member 1
B: Maltose/maltodextrin-binding periplasmic protein,Transient receptor potential cation channel subfamily V member 1
C: Maltose/maltodextrin-binding periplasmic protein,Transient receptor potential cation channel subfamily V member 1
D: Maltose/maltodextrin-binding periplasmic protein,Transient receptor potential cation channel subfamily V member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)563,63410
Polymers561,8664
Non-polymers1,7686
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Maltose/maltodextrin-binding periplasmic protein,Transient receptor potential cation channel subfamily V member 1 / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / TrpV1 / Capsaicin receptor / ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / TrpV1 / Capsaicin receptor / Osm-9-like TRP channel 1 / OTRPC1 / Vanilloid receptor 1 / Vanilloid receptor type 1-like


Mass: 140466.562 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli K-12 (bacteria), (gene. exp.) Rattus norvegicus (Norway rat)
Gene: malE, b4034, JW3994, Trpv1, Vr1, Vr1l / Production host: Homo sapiens (human) / References: UniProt: P0AEX9, UniProt: O35433
#2: Chemical
ChemComp-A1D6R / ~{N}-[4-[6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]oxy-1,3-benzothiazol-2-yl]ethanamide / AMG-517


Mass: 430.403 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H13F3N4O2S
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: ratTRPV1 bound with antagonist AMG517 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 45 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.20.1_4487model refinement
13PHENIX3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 368794 / Symmetry type: POINT
RefinementHighest resolution: 2.7 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00717972
ELECTRON MICROSCOPYf_angle_d0.76124340
ELECTRON MICROSCOPYf_dihedral_angle_d6.5122376
ELECTRON MICROSCOPYf_chiral_restr0.042712
ELECTRON MICROSCOPYf_plane_restr0.0083012

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