A maurotoxin with constrained standard disulfide bridging: innovative strategy of chemical synthesis, pharmacology, and docking on K+ channels.
Maurotoxin (MTX) is a 34-residue toxin that has been isolated initially from the venom of the scorpion Scorpio maurus palmatus. It presents a large number of pharmacological targets, including small conductance Ca2+-activated and voltage-gated K+ channels. Contrary to other toxins of the alpha-KTx6 family (Pi1, Pi4, Pi7, and HsTx1), MTX exhibits a unique disulfide bridge organization of the type C1-C5, C2-C6, C3-C4, and C7-C8 (instead of the conventional C1-C5, C2-C6, C3-C7, and C4-C8, herein referred to as Pi1-like) that does not prevent its folding along the classic alpha/beta scaffold of scorpion toxins. Here, we developed an innovative strategy of chemical peptide synthesis to produce an MTX variant (MTXPi1) with a conventional pattern of disulfide bridging without any alteration of the toxin chemical structure. This strategy was used solely to address the impact of half-cystine pairings on MTX structural properties and pharmacology. The data indicate that MTXPi1 displays some marked changes in affinities toward the target K+ channels. Computed docking analyses using molecular models of both MTXPi1 and the various voltage-gated K+ channel subtypes (Shaker B, Kv1.2, and Kv1.3) were found to correlate with MTXPi1 pharmacology. A functional map detailing the interaction between MTXPi1 and Shaker B channel was generated in line with docking experiments.
M'Barek
Sarrah
S
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS Unité Mixte de Recherche 6560 Bd Pierre Dramard, 13916 Marseille Cedex 20, France.
Lopez-Gonzalez
Ignacio
I
Andreotti
Nicolas
N
di Luccio
Eric
E
Visan
Violeta
V
Grissmer
Stephan
S
Judge
Susan
S
El Ayeb
Mohamed
M
Darbon
Hervé
H
Rochat
Hervé
H
Sampieri
François
F
Béraud
Evelyne
E
Fajloun
Ziad
Z
De Waard
Michel
M
Sabatier
Jean-Marc
JM
D000595:Amino Acid Sequence; D000818:Animals; D001030:Apamin / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D004220:Disulfides / Q000737:chemistry*; D007457:Iodine Radioisotopes; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D012604:Scorpion Venoms / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D012605:Scorpions / Q000737:chemistry*; D020539:Sequence Analysis, Protein; D051637:Shaker Superfamily of Potassium Channels; D013574:Synaptosomes / Q000187:drug effects; D014981:Xenopus
D004220:Disulfides; D007457:Iodine Radioisotopes; C104751:Pi1 toxin; D015221:Potassium Channels; D012604:Scorpion Venoms; D051637:Shaker Superfamily of Potassium Channels; C104498:maurotoxin; D001030:Apamin