期刊
MARINE DRUGS
卷 17, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/md17070390
关键词
mu-conotoxin; PIIIA; voltage-gated sodium channel; disulfide connectivity; peptide folding; electrophysiology; molecular docking; molecular dynamics
资金
- University of Bonn
Cyclic mu-conotoxin PIIIA, a potent blocker of skeletal muscle voltage-gated sodium channel Na(V)1.4, is a 22mer peptide stabilized by three disulfide bonds. Combining electrophysiological measurements with molecular docking and dynamic simulations based on NMR solution structures, we investigated the 15 possible 3-disulfide-bonded isomers of mu-PIIIA to relate their blocking activity at Na(V)1.4 to their disulfide connectivity. In addition, three mu-PIIIA mutants derived from the native disulfide isomer, in which one of the disulfide bonds was omitted (C4-16, C5-C21, C11-C22), were generated using a targeted protecting group strategy and tested using the aforementioned methods. The 3-disulfide-bonded isomers had a range of different conformational stabilities, with highly unstructured, flexible conformations with low or no channel-blocking activity, while more constrained molecules preserved 30% to 50% of the native isomer's activity. This emphasizes the importance and direct link between correct fold and function. The elimination of one disulfide bond resulted in a significant loss of blocking activity at Na(V)1.4, highlighting the importance of the 3-disulfide-bonded architecture for mu-PIIIA. mu-PIIIA bioactivity is governed by a subtle interplay between an optimally folded structure resulting from a specific disulfide connectivity and the electrostatic potential of the conformational ensemble.
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