A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin

Abstract

Insulins in the venom of certain fish-hunting cone snails facilitate prey capture by rapidly inducing hypoglycemic shock. One such insulin, Conus geographus G1 (Con-Ins G1), is the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin, mediates engagement of the insulin receptor and assembly of the hormone's hexameric storage form. Removal of this segment (residues B23-B30) in human insulin results in substantial loss of receptor affinity. Here, we found that Con-Ins G1 is monomeric, strongly binds the human insulin receptor and activates receptor signaling. Con-Ins G1 thus is a naturally occurring B-chain-minimized mimetic of human insulin. Our crystal structure of Con-Ins G1 reveals a tertiary structure highly similar to that of human insulin and indicates how Con-Ins G1's lack of an equivalent to the key receptor-engaging residue Phe is mitigated. These findings may facilitate efforts to design ultrarapid-acting therapeutic insulins.

Peptides, Peptidomimetics, and Polypeptides from Marine Sources: A Wealth of Natural Sources for Pharmaceutical Applications

“…Insulin from Conus geographus G1 (Con-Ins G1) has similarities to human and fish insulin, but lacks the C -terminal segment of the B chain of human insulin. Smith et al [147] elucidated the structural details of insulin from Conus geographus G1 and showed that Con-Ins G1 binds to the human insulin receptor and activates human insulin. Additionally, the peptide was found to be in monomeric form, acting as a mimetic of human insulin.…”

Linking neuroethology to the chemical biology of natural products: interactions between cone snails and their fish prey, a case study

“…When added to water, this venom insulin elicits hypoactivity in fish (Safavi-Hemami et al 2015b). It was demonstrated that this venom component (Con-Ins G1) causes blood glucose levels to fall through binding the fish insulin receptor (Safavi-Hemami et al 2015b), and even potently binds to the human insulin receptor (Menting et al 2016). As will be discussed in more detail below, this insulin has striking similarity in its sequence and structure to fish insulin (and is very divergent from the native insulins used for insulin signaling in the snail itself).…”

“…As will be discussed in more detail below, this insulin has striking similarity in its sequence and structure to fish insulin (and is very divergent from the native insulins used for insulin signaling in the snail itself). Notably, unlike endogenous fish insulins that are secreted by the β-cells of the pancreas as hexameric complexes, designed to act over a long period of time, the cone snail insulin is a monomer that acts very quickly (Menting et al 2016), reflecting its streamlined role in prey capture. When tested in zebrafish, after the insulin is released into the water, it immediately impairs the swimming behavior of fish (Safavi-Hemami et al 2015b), and is presumably taken up through the gills of the fish from which it rapidly enters the blood stream.…”

“…Similarities between Con-ins G1 and fish insulins are lower in the B chain (~70%). However, these differences render Con-Ins G1 faster acting than fish insulin and highlight its streamlined role for predation (Menting et al 2016). Similarly, mollusc-hunting snails, such as Conus textile and Conus marmoreus , express a venom insulin that has more similarities to endogenous molluscan insulins than to any other group, including fish and worm insulins (Safavi-Hemami et al 2015b).…”

Venom evolution provides inspiration for development of ultrafast-acting insulins

“…One such insulin possesses a striking difference to other types present both in the snail and vertebrates in that it bears posttranslational modifications and, most striking, truncations that result in the absence of a B-chain C-terminal motif that has been shown to be essential for the engagement of insulin by the tandem-binding element that constitutes the primary binding site of the insulin receptor (IR). Whilst engagement of the cone snail insulin to human IR is substantially weaker than for native human insulin it nevertheless indicates that the cone snail insulin has features that somewhat overcome the absence of this motif [1]. For many decades therapeutic insulins have been developed to overcome the limitations of native insulin as a therapeutic agent.…”