| Literature DB >> 27026701 |
Jennifer R Deuis1, Zoltan Dekan2, Marco C Inserra1, Tzong-Hsien Lee3, Marie-Isabel Aguilar3, David J Craik2, Richard J Lewis2, Paul F Alewood2, Mehdi Mobli4, Christina I Schroeder5, Sónia Troeira Henriques6, Irina Vetter7.
Abstract
The μO-conotoxins MrVIA, MrVIB, and MfVIA inhibit the voltage-gated sodium channel NaV1.8, a well described target for the treatment of pain; however, little is known about the residues or structural elements that define this activity. In this study, we determined the three-dimensional structure of MfVIA, examined its membrane binding properties, performed alanine-scanning mutagenesis, and identified residues important for its activity at human NaV1.8. A second round of mutations resulted in (E5K,E8K)MfVIA, a double mutant with greater positive surface charge and greater affinity for lipid membranes compared with MfVIA. This analogue had increased potency at NaV1.8 and was analgesic in the mouse formalin assay.Entities:
Keywords: NaV1.8; lipid-protein interaction; mutagenesis; pain; peptide chemical synthesis; sodium channel; structure-activity relationships; μO-conotoxin MfVIA
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Year: 2016 PMID： 27026701 PMCID： PMC4882450 DOI： 10.1074/jbc.M116.721662
Source DB: PubMed Journal: J Biol Chem ISSN： 0021-9258 Impact factor: 5.157