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- EMDB-21127: Structure of TRPA1 modified by Bodipy-iodoacetamide with bound ca... -

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Basic information

Entry
Database: EMDB / ID: EMD-21127
TitleStructure of TRPA1 modified by Bodipy-iodoacetamide with bound calcium, LMNG
Map dataFull map
Sample
  • Complex: TRPA1 modified by Bodipy-iodoacetamide with bound calcium, solubilized in LMNG
    • Protein or peptide: Transient receptor potential cation channel subfamily A member 1
  • Ligand: ~{N}-[[2,2-bis(fluoranyl)-10,12-dimethyl-1,3-diaza-2$l^{4}-boratricyclo[7.3.0.0^{3,7}]dodeca-4,6,9,11-tetraen-4-yl]methyl]ethanamide
  • Ligand: CALCIUM ION
Keywordstransient receptor potential subfamily A member 1 / Membrane protein / TRANSPORT 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 / cellular response to caffeine / response to pain / calcium ion transmembrane import into cytosol / TRP channels / cellular response to cold / 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: 2.6 Å
AuthorsZhao J / Lin King JV / Paulsen CE / Cheng Y / Julius D
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R35 NS105038 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM098672 United States
CitationJournal: Nature / Year: 2020
Title: Irritant-evoked activation and calcium modulation of the TRPA1 receptor.
Authors: Jianhua Zhao / John V Lin King / Candice E Paulsen / Yifan Cheng / David Julius /
Abstract: The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, ...The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids. TRPA1 is also a 'receptor-operated' channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch, making it an attractive target for novel analgesic therapies. However, the mechanisms by which TRPA1 recognizes and responds to electrophiles or cytoplasmic second messengers remain unknown. Here we use strutural studies and electrophysiology to show that electrophiles act through a two-step process in which modification of a highly reactive cysteine residue (C621) promotes reorientation of a cytoplasmic loop to enhance nucleophilicity and modification of a nearby cysteine (C665), thereby stabilizing the loop in an activating configuration. These actions modulate two restrictions controlling ion permeation, including widening of the selectivity filter to enhance calcium permeability and opening of a canonical gate at the cytoplasmic end of the pore. We propose a model to explain functional coupling between electrophile action and these control points. We also characterize a calcium-binding pocket that is highly conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization and activation by metabotropic receptors. These findings provide a structural framework for understanding how a broad-spectrum irritant receptor is controlled by endogenous and exogenous agents that elicit or exacerbate pain and itch.
History
DepositionDec 16, 2019-
Header (metadata) releaseJan 15, 2020-
Map releaseMay 6, 2020-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 4
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 4
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6v9v
  • Surface level: 7
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
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Supplemental images

emd_21127.png

Downloads & links

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Map

FileDownload / File: emd_21127.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.22 Å/pix.
x 256 pix.
= 311.194 Å		1.22 Å/pix.
x 256 pix.
= 311.194 Å		1.22 Å/pix.
x 256 pix.
= 311.194 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.2156 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.8 / Movie #1: 4
Minimum - Maximum-11.545505 - 34.040806000000003
Average (Standard dev.)-0.000000035498093 (±0.9999951)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 311.1936 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.21560156251.21560156251.2156015625
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z311.194311.194311.194
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-11.54634.041-0.000

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Supplemental data

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Mask #1

Fileemd_21127_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1

Fileemd_21127_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_21127_half_map_2.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram (log scale)

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Sample components

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Entire : TRPA1 modified by Bodipy-iodoacetamide with bound calcium, solubi...

EntireName: TRPA1 modified by Bodipy-iodoacetamide with bound calcium, solubilized in LMNG
Components
  • Complex: TRPA1 modified by Bodipy-iodoacetamide with bound calcium, solubilized in LMNG
    • Protein or peptide: Transient receptor potential cation channel subfamily A member 1
  • Ligand: ~{N}-[[2,2-bis(fluoranyl)-10,12-dimethyl-1,3-diaza-2$l^{4}-boratricyclo[7.3.0.0^{3,7}]dodeca-4,6,9,11-tetraen-4-yl]methyl]ethanamide
  • Ligand: CALCIUM ION

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Supramolecule #1: TRPA1 modified by Bodipy-iodoacetamide with bound calcium, solubi...

SupramoleculeName: TRPA1 modified by Bodipy-iodoacetamide with bound calcium, solubilized in LMNG
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: 127.646539 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKRSLRKMWR PGEKKEPQGV VYEDVPDDTE DFKESLKVVF EGSAYGLQNF NKQKKLKRCD DMDTFFLHYA AAEGQIELME KITRDSSLE VLHEMDDYGN TPLHCAVEKN QIESVKFLLS RGANPNLRNF NMMAPLHIAV QGMNNEVMKV LLEHRTIDVN L EGENGNTA ...String:
MKRSLRKMWR PGEKKEPQGV VYEDVPDDTE DFKESLKVVF EGSAYGLQNF NKQKKLKRCD DMDTFFLHYA AAEGQIELME KITRDSSLE VLHEMDDYGN TPLHCAVEKN QIESVKFLLS RGANPNLRNF NMMAPLHIAV QGMNNEVMKV LLEHRTIDVN L EGENGNTA VIIACTTNNS EALQILLKKG AKPCKSNKWG CFPIHQAAFS GSKECMEIIL RFGEEHGYSR QLHINFMNNG KA TPLHLAV QNGDLEMIKM CLDNGAQIDP VEKGRCTAIH FAATQGATEI VKLMISSYSG SVDIVNTTDG CHETMLHRAS LFD HHELAD YLISVGADIN KIDSEGRSPL ILATASASWN IVNLLLSKGA QVDIKDNFGR NFLHLTVQQP YGLKNLRPEF MQMQ QIKEL VMDEDNDGCT PLHYACRQGG PGSVNNLLGF NVSIHSKSKD KKSPLHFAAS YGRINTCQRL LQDISDTRLL NEGDL HGMT PLHLAAKNGH DKVVQLLLKK GALFLSDHNG WTALHHASMG GYTQTMKVIL DTNLKCTDRL DEDGNTALHF AAREGH AKA VALLLSHNAD IVLNKQQASF LHLALHNKRK EVVLTIIRSK RWDECLKIFS HNSPGNKCPI TEMIEYLPEC MKVLLDF CM LHSTEDKSCR DYYIEYNFKY LQCPLEFTKK TPTQDVIYEP LTALNAMVQN NRIELLNHPV CKEYLLMKWL AYGFRAHM M NLGSYCLGLI PMTILVVNIK PGMAFNSTGI INETSDHSEI LDTTNSYLIK TCMILVFLSS IFGYCKEAGQ IFQQKRNYF MDISNVLEWI IYTTGIIFVL PLFVEIPAHL QWQCGAIAVY FYWMNFLLYL QRFENCGIFI VMLEVILKTL LRSTVVFIFL LLAFGLSFY ILLNLQDPFS SPLLSIIQTF SMMLGDINYR ESFLEPYLRN ELAHPVLSFA QLVSFTIFVP IVLMNLLIGL A VGDIADVQ KHASLKRIAM QVELHTSLEK KLPLWFLRKV DQKSTIVYPN KPRSGGMLFH IFCFLFCTGE IRQEIPNADK SL EMEILKQ KYRLKDLTFL LEKQHELIKL IIQKMEIISE TEDDDSHCSF QDRFKKEQME QRNSRWNTVL RAVKAKTHHL EP

UniProtKB: Transient receptor potential cation channel subfamily A member 1

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Macromolecule #2: ~{N}-[[2,2-bis(fluoranyl)-10,12-dimethyl-1,3-diaza-2$l^{4}-boratr...

MacromoleculeName: ~{N}-[[2,2-bis(fluoranyl)-10,12-dimethyl-1,3-diaza-2$l^{4}-boratricyclo[7.3.0.0^{3,7}]dodeca-4,6,9,11-tetraen-4-yl]methyl]ethanamide
type: ligand / ID: 2 / Number of copies: 4 / Formula: QT4
Molecular weightTheoretical: 292.112 Da
Chemical component information

ChemComp-QT4:
~{N}-[[2,2-bis(fluoranyl)-10,12-dimethyl-1,3-diaza-2$l^{4}-boratricyclo[7.3.0.0^{3,7}]dodeca-4,6,9,11-tetraen-4-yl]methyl]ethanamide

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Macromolecule #3: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 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

BufferpH: 8
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 25.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 212751
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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