Figure 6 : Sequence analysis of vasopressin-sensitive receptors. In bold, residues which are identical between rat (r) and human (h) V2Rs but variable in hV1aR, hV1bR or hOT. Red: acidic residues. Orange: non-polar residues. ECL: extracellular loop.
The Kunitz structure is active on 3 major classes of molecular targets: enzymes, channels and receptors. It is a rare situation in animal toxins where each structure is linked in great part to only one activity. Only the 3FT family, exclusively produced by snakes, target also these 3 classes of proteins that are enzymes (serine proteases for BPTI, acetylcholine esterase for fasciculins, Bourne et al., 1995), ion channels (Kv1.1 for the dendrotoxins, ASIC channel for the mambalgins, Sun et al., 2018) and GPCRs (V2R for MQ1, Muscarinic and adrenergic receptors for aminergic toxins, Quinton et al., 2010; Rouget et al., 2010; Blanchet et al., 2017). The 3FT toxins are composed of 3 loops called fingers linked by a structured part rich in disulfide bridges (Fruchart-Gaillard et al., 2012). 3FTs always use their fingers to interact with their targets. The fasciculins and the mambalgins use their first and second fingers while the MT7 uses all of its 3 fingers (Maeda et al., 2020). The Kunitz peptides show much more adaptive binding strategies. For each target class, a distinct mode of action is used by these peptides. The mode of interaction of MQ1 to bind V2R is particularly efficient as MQ1 is the most selective V2R ligand ever described.