The recent discovery that viruses from the Iridoviridae family carry sequences encoding insulin-like proteins is astonishing, as such viral insulin-like proteins (VILPs) may be implicated in disease through their interaction with human insulin- or insulin-like growth factor receptors, or through their induction of an auto-immune response [1]. Critically, DNA sequences from these viruses have been detected in the human faecal virome and in circulating human blood, likely resulting from the ingestion of infected fish (the natural host) [1].
A particularly interesting viral insulin-like protein is that of lymphocystis disease virus-1 (LCDV-1). We term this protein "scLCDV1-VILP", reflecting that we have studied it as a single-chain ("sc") polypeptide analogous to human insulin-like growth factors (hIGF-I, -II), rather than as a double-chain polypeptide analogous to human insulin. scLCDV1-VILP binds to the human type 1 insulin-like receptor (hIGF-1R) with affinity approximately ten-fold lower than hIGF-I and is a partial agonist [1]. However, scLCDV1-VILP is a competitive antagonist of hIGF-1R at high concentrations [2]. Understanding the basis for such antagonism may have implications for the design of IGF-1R-specific therapeutics in the context of cancer, especially as scLCDV1-VILP has very limited ability to stimulate the insulin receptor [1].
We show here, using single-particle cryo-electron microscopy (cryoEM), that the antagonistic properties of scLCDV1-VILP arise from its non-engagement with the receptor's membrane-distal regions (termed "site 1b"). Indeed, single hIGF-I (or hIGF-II) crosslinking of the primary binding site to site 1b is required to effect the structural transitions in the receptor that bring about signal transduction [3; 4]. Our cryoEM structure reveals instead a dual primary-site liganded hIGF-1R homodimer, but neither scLCDV1-VILP engages site 1b and the receptor does not assume a signalling-active conformation. Data from chimeric scLCDV1-VILP / hIGF-I studies then enable us to deduce a possible source of the VILP's inability to engage site 1b [2].