Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Irritant-evoked activation and calcium modulation of the TRPA1 receptor.
Journal, issue, pages	Nature, Vol. 585, Issue 7823, Page 141-145, Year 2020
Publish date	Jul 8, 2020
Authors	Jianhua Zhao / John V Lin King / Candice E Paulsen / Yifan Cheng / David Julius /
PubMed 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.
External links	Nature / PubMed:32641835 / PubMed Central
Methods	EM (single particle)
Resolution	2.6 - 5.9 Å
Structure data	21127 6v9v EMDB-21127, PDB-6v9v: Structure of TRPA1 modified by Bodipy-iodoacetamide with bound calcium, LMNG Method: EM (single particle) / Resolution: 2.6 Å 21128 6v9w EMDB-21128, PDB-6v9w: Structure of TRPA1 (ligand-free) with bound calcium, LMNG Method: EM (single particle) / Resolution: 3.1 Å 21129 6v9x EMDB-21129, PDB-6v9x: Structure of TRPA1 modified by iodoacetamide, PMAL-C8 Method: EM (single particle) / Resolution: 3.3 Å 21130 6v9y EMDB-21130, PDB-6v9y: Structure of TRPA1 bound with A-967079, PMAL-C8 Method: EM (single particle) / Resolution: 3.6 Å EMDB-21131: Structure of TRPA1 treated with A-967079 (class 2), PMAL-C8 Method: EM (single particle) / Resolution: 3.5 Å EMDB-21537: TRPA1 (ligand-free and calcium-free) in PMAL-C8, class 1 Method: EM (single particle) / Resolution: 5.9 Å EMDB-21538: Structure of TRPA1 (ligand-free and calcium-free), PMAL-C8, class 2 Method: EM (single particle) / Resolution: 4.3 Å
Chemicals	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 ChemComp-CA: Unknown entry
Source	homo sapiens (human)
Keywords	TRANSPORT PROTEIN / transient receptor potential subfamily A member 1 / Membrane protein / Transient receptor potential cation channel subfamily A member 1