Investigation of Binding Modes and Functional Surface of Scorpion Toxins ANEP to Sodium Channels 1.7

Abstract

The depressant β toxin anti-neuroexcitation peptide (ANEP) from the Chinese scorpion Buthus martensii Karsch has analgesic activity by interacting with receptor site 4 of the voltage-gated sodium channels (VGSCs). Here, with molecular dynamics simulations, we examined the binding modes between ANEP and the site 4 of mice sodium channel 1.7 (mNav1.7), a subtype of VGSCs related to peripheral pain. Homology modeling, molecular mechanics, and molecular dynamics in the biomembrane environment were adopted. The results suggested that ANEP bound to the resting site 4 mainly by amino acid residues in the β2–β3 loop and the ‘NC’ domains, and the activate site 4 mainly by amino acid residues in the hydrophobic domain of N-groove and residues in the ‘pharmacophore’. Effects analysis of 14 mutants in the predicted functional domains of ANEP on mouse twisting models showed that the analgesic activity of mutants L15 and E24 of the ‘pharmacophore’, W36, T37, W38, and T39 forming the loop between the β2- and β3-strands and N8, V12, C60, and K64 in the NC domain increased distinctly after these residues were substituted for Ala, respectively. The binding modes and the active sites predicted were consistent with available mutagenesis data, and which is meaningful to understand the related mechanisms of ANEP for Nav1.7.

Peptides with Diverse Functions from Scorpion Venom: A Great Opportunity for the Treatment of a Wide Variety of Diseases

“…AGAP also alters Nav1.7 channel [140] . ANEP has shown the same activity in a mouse-twisting model and the hot plate assay by inhibiting Nav1.7 channel [141] . BmK AGP-SYPU1 [142] and BmK AGP-SYPU2, two analgesic peptides [143] extracted from a Chinese scorpion, are significantly activated by adding the arginine [144] and glycine [145] residues in the Cterminal region, respectively.…”

“…BmK AGP-SYPU1 [142] and BmK AGP-SYPU2, two analgesic peptides [143] extracted from a Chinese scorpion, are significantly activated by adding the arginine [144] and glycine [145] residues in the Cterminal region, respectively. Recombinant (rBmKM9) BmK-YA B. martensii Karsch Mammalian opioid receptors ( μ, δ and κ subtype) [137] (BmK) AngM1 B. martensii Karsch Nav, Kv [138] BmK AGAP B. martensii Karsch Nav 1.7 [139] ANEP B. martensii Karsch Nav1.7 [141] BmK AGP-SYPU1 B. martensii Karsch - [142] BmK AGP-SYPU2 B. martensii Karsch - [167] BmKM9 (rBmKM9) B. martensii Karsch Nav1.4, Nav1.5, Nav1.7 [146] Amm VIII A. mauretanicus Nav 1.2 [148] TsNTxP T. serrulatus Nav [149] Hetlaxin H. laoticus Kv1.3 [150] Leptucin H. lepturus - [151] Iran. Biomed.…”

Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

“…Mutation of Trp38, a link between the two active surfaces of the peptide, can critically affect the structural stability of the peptide and also its analgesic properties [ 34 , 147 ]. Many other similar peptides (BmK AGP-SYPU1, BmK AGP-SYPU2) but also the insect selective (BmK IT-AP, BmKITAP3), ANEP toxin and BmK AngM1 display analgesic properties [ 33 , 138 , 148 - 150 ]. The exact interaction of these toxins with Nav remains unclear.…”

Peptides with Diverse Functions from Scorpion Venom: A Great Opportunity for the Treatment of a Wide Variety of Diseases

“…AGAP also alters Nav1.7 channel [ 140 ] . ANEP has shown the same activity in a mouse-twisting model and the hot plate assay by inhibiting Nav1.7 channel [ 141 ] . BmK AGP-SYPU1 [ 142 ] and BmK AGP-SYPU2, two analgesic peptides [ 143 ] extracted from a Chinese scorpion, are significantly activated by adding the arginine [ 144 ] and glycine [ 145 ] residues in the C- terminal region, respectively.…”