RT info:eu-repo/semantics/article
T1 Identification of a critical binding site for local anaesthetics in the side pockets of Kv1 channels
A1 Kiper, Aytug K.
A1 Bedoya, Mauricio
A1 Stalke, Sarah
A1 Marzian, Stefanie
A1 Ramírez, David
A1 de la Cruz, Alicia
A1 Peraza, Diego A.
A1 Vera‐Zambrano, Alba
A1 Márquez Montesinos, José C. E.
A1 Arévalo Ramos, Bárbara A.
A1 Rinné, Susanne
A1 Gonzalez, Teresa
A1 Valenzuela, Carmen
A1 Gonzalez, Wendy
A1 Decher, Niels
AB 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.Experimental approach: 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.Key results: 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.
SN 0007-1188
YR 2021
FD 2021
LK https://uvadoc.uva.es/handle/10324/66030
UL https://uvadoc.uva.es/handle/10324/66030
LA spa
NO Br J Pharmacol . 2021 Aug;178(15):3034-3048. doi: 10.1111/bph.15480. Epub 2021 May 14.
DS UVaDOC
RD 28-nov-2024