Identification of a critical binding site for local anaesthetics in the side pockets of Kv 1 channels.
Br J Pharmacol
; 178(15): 3034-3048, 2021 08.
Article
en En
| MEDLINE
| ID: mdl-33817777
ABSTRACT
BACKGROUND AND PURPOSE:
Local anaesthetics block sodium and a variety of potassium channels. Although previous studies identified a residue in the pore signature sequence together with three residues in the S6 segment as a putative binding site, the precise molecular basis of inhibition of Kv channels by local anaesthetics remained unknown. Crystal structures of Kv channels predict that some of these residues point away from the central cavity and face into a drug binding site called side pockets. Thus, the question arises whether the binding site of local anaesthetics is exclusively located in the central cavity or also involves the side pockets. EXPERIMENTALAPPROACH:
A systematic functional alanine mutagenesis approach, scanning 58 mutants, together with in silico docking experiments and molecular dynamics simulations was utilized to elucidate the binding site of bupivacaine and ropivacaine. KEYRESULTS:
Inhibition of Kv 1.5 channels by local anaesthetics requires binding to the central cavity and the side pockets, and the latter requires interactions with residues of the S5 and the back of the S6 segments. Mutations in the side pockets remove stereoselectivity of inhibition of Kv 1.5 channels by bupivacaine. Although binding to the side pockets is conserved for different local anaesthetics, the binding mode in the central cavity and the side pockets shows considerable variations. CONCLUSION AND IMPLICATIONS Local anaesthetics bind to the central cavity and the side pockets, which provide a crucial key to the molecular understanding of their Kv channel affinity and stereoselectivity, as well as their spectrum of side effects.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Canales de Potasio
/
Anestésicos Locales
Tipo de estudio:
Diagnostic_studies
Límite:
Humans
Idioma:
En
Revista:
Br J Pharmacol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Alemania