Functional dynamics and allosteric modulation of TRPA1.
Structure
; 31(12): 1556-1566.e3, 2023 12 07.
Article
en En
| MEDLINE
| ID: mdl-37729917
ABSTRACT
The cation channel TRPA1 is a potentially important drug target, and characterization of TRPA1 functional dynamics might help guide structure-based drug design. Here, we present results from long-timescale molecular dynamics simulations of TRPA1 with an allosteric activator, allyl isothiocyanate (AITC), in which we observed spontaneous transitions from a closed, non-conducting channel conformation into an open, conducting conformation. Based on these transitions, we propose a gating mechanism in which movement of a regulatory TRP-like domain allosterically translates into pore opening in a manner reminiscent of pore opening in voltage-gated ion channels. In subsequent experiments, we found that mutations that disrupt packing of the S4-S5 linker-TRP-like domain and the S5 and S6 helices also affected channel activity. In simulations, we also observed A-967079, a known allosteric inhibitor, binding between helices S5 and S6, suggesting that A-967079 may suppress activity by stabilizing a non-conducting pore conformation-a finding consistent with our proposed gating mechanism.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Oximas
Idioma:
En
Revista:
Structure
Asunto de la revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
BIOTECNOLOGIA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos