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- EMDB-48457: Preclinical and clinical evaluation of a novel TRPA1 antagonist L... -

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Basic information

Entry
Database: EMDB / ID: EMD-48457
TitlePreclinical and clinical evaluation of a novel TRPA1 antagonist LY3526318
Map data
Sample
  • Complex: tetrameric ion channel TrpA1
    • Protein or peptide: Transient receptor potential cation channel subfamily A member 1
  • Ligand: (2S)-2-{3-methyl-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}-N-{6-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl}propanamide
KeywordsPain receptor / TrpA1 / ion channel / ligand gating / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of blood circulation / positive regulation of monoatomic anion transport / cellular response to food / temperature-gated cation channel activity / regulation of neuronal action potential / cellular response to carbon dioxide / osmolarity-sensing monoatomic cation channel activity / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / urinary bladder smooth muscle contraction ...regulation of blood circulation / positive regulation of monoatomic anion transport / cellular response to food / temperature-gated cation channel activity / regulation of neuronal action potential / cellular response to carbon dioxide / osmolarity-sensing monoatomic cation channel activity / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / urinary bladder smooth muscle contraction / thermoception / cellular response to toxic substance / TRP channels / calcium ion transmembrane import into cytosol / response to pain / cellular response to cold / cellular response to caffeine / intracellularly gated calcium channel activity / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of insulin secretion involved in cellular response to glucose stimulus / voltage-gated calcium channel activity / monoatomic ion transport / sensory perception of pain / response to cold / calcium ion transmembrane transport / calcium channel activity / cellular response to hydrogen peroxide / intracellular calcium ion homeostasis / cellular response to heat / channel activity / protein homotetramerization / cell surface receptor signaling pathway / apical plasma membrane / response to xenobiotic stimulus / axon / identical protein binding / plasma membrane
Similarity search - Function
: / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / 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 A member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsNie S
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Pain / Year: 2025
Title: Preclinical and clinical evaluation of a novel TRPA1 antagonist LY3526318.
Authors: Lisa M Broad / Jeffrey G Suico / P Kellie Turner / Si Nie / Kirk W Johnson / Helen E Sanger / Lindsay A Wegiel / David C Sperry / David Remick / Magdalene Moran / Sam Malekiani / Donato Del ...Authors: Lisa M Broad / Jeffrey G Suico / P Kellie Turner / Si Nie / Kirk W Johnson / Helen E Sanger / Lindsay A Wegiel / David C Sperry / David Remick / Magdalene Moran / Sam Malekiani / Donato Del Camino / Xinyuan Wu / Jayhong A Chong / Nathaniel T Blair / August V Wilke /
Abstract: The transient receptor potential cation channel member A1 (TRPA1) is heavily implicated in nociceptive signaling in both physiological and pathological pain states. However, it has been challenging ...The transient receptor potential cation channel member A1 (TRPA1) is heavily implicated in nociceptive signaling in both physiological and pathological pain states. However, it has been challenging to develop TRPA1 antagonists with appropriate properties to advance into clinical development. Herein, we describe the preclinical characterization and early clinical development of LY3526318, a potent, selective, and orally bioavailable TRPA1 antagonist. In vitro studies showed that LY3526318 reversibly inhibited recombinant TRPA1 channels with nanomolar potency that was conserved across species. LY3526318 also inhibited the function of native human and rat TRPA1 channels, including nociceptive dorsal root ganglion neuronal TRPA1 channels. In vivo studies showed that LY3526318 blocked formalin-evoked flinching behaviors and chronic Freund adjuvant-induced cold hypersensitivity in rats. Only male rats were used in these studies. Initial phase 1, single- and multiple-ascending dose studies evaluating pharmacokinetic and safety parameters of LY3526318 revealed a suboptimal pharmacokinetic profile leading to the development and study of a spray-dried dispersion (SDD) formulation of LY3526318. When dosed once daily at 250 mg, LY3526318-SDD showed a t max of 4 hours and t 1/2 of 12 hours, maintaining plasma exposures demonstrated to engage the TRPA1 target. Adverse events were transient and mild across all phase 1 studies. In summary, LY3526318 blocked TRPA1 in vitro and in vivo, inhibited behavioral signs of enhanced nociception in animal models, and was safe and well tolerated in phase 1 clinical studies, with LY3526318-SDD displaying an appropriate pharmacokinetic profile to advance to proof-of-concept studies in patients with chronic pain.
History
DepositionDec 26, 2024-
Header (metadata) releaseMay 21, 2025-
Map releaseMay 21, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48457.png

Downloads & links

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Map

FileDownload / File: emd_48457.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 352 pix.
= 371.008 Å		1.05 Å/pix.
x 352 pix.
= 371.008 Å		1.05 Å/pix.
x 352 pix.
= 371.008 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.054 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-2.9159987 - 3.7884881
Average (Standard dev.)0.00080541085 (±0.07617042)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 371.008 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_48457_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_48457_half_map_2.map
Projections & Slices
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Sample components

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Entire : tetrameric ion channel TrpA1

EntireName: tetrameric ion channel TrpA1
Components
  • Complex: tetrameric ion channel TrpA1
    • Protein or peptide: Transient receptor potential cation channel subfamily A member 1
  • Ligand: (2S)-2-{3-methyl-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}-N-{6-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl}propanamide

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Supramolecule #1: tetrameric ion channel TrpA1

SupramoleculeName: tetrameric ion channel TrpA1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 684 KDa

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Macromolecule #1: Transient receptor potential cation channel subfamily A member 1

MacromoleculeName: Transient receptor potential cation channel subfamily A member 1
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.699586 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LGKRSLRKMW RPGEKKEPQG VVYEDVPDDT EDFKESLKVV FEGSAYGLQN FNKQKKLKRC DDMDTFFLHY AAAEGQIELM EKITRDSSL EVLHEMDDYG NTPLHCAVEK NQIESVKFLL SRGANPNLRN FNMMAPLHIA VQGMNNEVMK VLLEHRTIDV N LEGENGNT ...String:
LGKRSLRKMW RPGEKKEPQG VVYEDVPDDT EDFKESLKVV FEGSAYGLQN FNKQKKLKRC DDMDTFFLHY AAAEGQIELM EKITRDSSL EVLHEMDDYG NTPLHCAVEK NQIESVKFLL SRGANPNLRN FNMMAPLHIA VQGMNNEVMK VLLEHRTIDV N LEGENGNT AVIIACTTNN SEALQILLKK GAKPCKSNKW GCFPIHQAAF SGSKECMEII LRFGEEHGYS RQLHINFMNN GK ATPLHLA VQNGDLEMIK MCLDNGAQID PVEKGRCTAI HFAATQGATE IVKLMISSYS GSVDIVNTTD GCHETMLHRA SLF DHHELA DYLISVGADI NKIDSEGRSP LILATASASW NIVNLLLSKG AQVDIKDNFG RNFLHLTVQQ PYGLKNLRPE FMQM QQIKE LVMDEDNDGC TPLHYACRQG GPGSVNNLLG FNVSIHSKSK DKKSPLHFAA SYGRINTCQR LLQDISDTRL LNEGD LHGM TPLHLAAKNG HDKVVQLLLK KGALFLSDHN GWTALHHASM GGYTQTMKVI LDTNLKCTDR LDEDGNTALH FAAREG HAK AVALLLSHNA DIVLNKQQAS FLHLALHNKR KEVVLTIIRS KRWDECLKIF SHNSPGNKCP ITEMIEYLPE CMKVLLD FC MLHSTEDKSC RDYYIEYNFK YLQCPLEFTK KTPTQDVIYE PLTALNAMVQ NNRIELLNHP VCKEYLLMKW LAYGFRAH M MNLGSYCLGL IPMTILVVNI KPGMAFNSTG IINETSDHSE ILDTTNSYLI KTCMILVFLS SIFGYCKEAG QIFQQKRNY FMDISNVLEW IIYTTGIIFV LPLFVEIPAH LQWQCGAIAV YFYWMNFLLY LQRFENCGIF IVMLEVILKT LLRSTVVFIF LLLAFGLSF YILLNLQDPF SSPLLSIIQT FSMMLGDINY RESFLEPYLR NELAHPVLSF AQLVSFTIFV PIVLMNLLIG L AVGDIAEV QKHASLKRIA MQVELHTSLE KKLPLWFLRK VDQKSTIVYP NKPRSGGMLF HIFCFLFCTG EIRQEIPNAD KS LEMEILK QKYRLKDLTF LLEKQHELIK LIIQKMEIIS ETEDDDSHCS FQDRFKKEQM EQRNSRWNTV LRAVKAKTHH LEP

UniProtKB: Transient receptor potential cation channel subfamily A member 1

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Macromolecule #2: (2S)-2-{3-methyl-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2,6-di...

MacromoleculeName: (2S)-2-{3-methyl-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}-N-{6-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl}propanamide
type: ligand / ID: 2 / Number of copies: 4 / Formula: A1BNO
Molecular weightTheoretical: 556.457 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration2 mg/mL
BufferpH: 8
Details: 20 mM HEPES, pH 8, 150 mM NaCl, 0.5 mM TCEP and 0.01% LMNG
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 18.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7jup

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 200000
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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