Sequence-specific 1H-NMR assignment and secondary structure of black mamba dendrotoxin I, a highly selective blocker of voltage-gated potassium channels.
The secondary structure of dendrotoxin I, an important constituent of the venom of the African black mamba snake Dendroaspis polylepis polylepis, was determined in aqueous solution by two-dimensional methods. Complete sequence-specific 1H-NMR assignment was obtained with the exception of the backbone amide proton of Gly39 and Cys40. Dendrotoxin I is based on a central antiparallel beta-sheet and two small helices located at the N- and the C-terminal extremities. These secondary-structural units occur at exactly the same places in the amino acid sequence as those of bovine pancreatic trypsin inhibitor (BPTI), with which dendrotoxin I shares 33% sequence similarity. According to the disulfide-bridge positions and the long-range NOE observed these secondary-structural elements fold in a similar manner to BPTI. This similarity allows an hypothesis according to which dendrotoxin I could derive from an ancestral Künitz-type proteinase inhibitor. This ancestor would have been heavily mutated at amino acid positions not critical for gross structure. The spatial locations of the solvent-exposed amino acids concerned could therefore serve as a guideline for interpretation of the structure/activity relationship of dendrotoxin I for the blockage of voltage-sensitive potassium channels of which dendrotoxin I is a strong inhibitor. The possible connections with other polypeptide toxins that block related ion currents is discussed.
Foray
M F
MF
Institut de Biologie Structurale, Grenoble, France.
Lancelin
J M
JM
Hollecker
M
M
Marion
D
D
D000595:Amino Acid Sequence; D007611:Aprotinin / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D004546:Elapid Venoms / Q000737:chemistry*; D004594:Electrophysiology; D015640:Ion Channel Gating; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry*; D015221:Potassium Channels / Q000187:drug effects*; D017433:Protein Structure, Secondary
D004220:Disulfides; D004546:Elapid Venoms; D009498:Neurotoxins; D015221:Potassium Channels; C020273:dendrotoxin; D007611:Aprotinin