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-Structure paper
Title | Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist. |
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Journal, issue, pages | Nat Commun, Vol. 13, Issue 1, Page 6700, Year 2022 |
Publish date | Nov 5, 2022 |
Authors | Francois Moreau / Nicholas S Kirk / Fa Zhang / Vasily Gelfanov / Edward O List / Martina Chrudinová / Hari Venugopal / Michael C Lawrence / Veronica Jimenez / Fatima Bosch / John J Kopchick / Richard D DiMarchi / Emrah Altindis / C Ronald Kahn / |
PubMed Abstract | Lymphocystis disease virus-1 (LCDV-1) and several other Iridoviridae encode viral insulin/IGF-1 like peptides (VILPs) with high homology to human insulin and IGFs. Here we show that while single- ...Lymphocystis disease virus-1 (LCDV-1) and several other Iridoviridae encode viral insulin/IGF-1 like peptides (VILPs) with high homology to human insulin and IGFs. Here we show that while single-chain (sc) and double-chain (dc) LCDV1-VILPs have very low affinity for the insulin receptor, scLCDV1-VILP has high affinity for IGF1R where it can antagonize human IGF-1 signaling, without altering insulin signaling. Consequently, scLCDV1-VILP inhibits IGF-1 induced cell proliferation and growth hormone/IGF-1 induced growth of mice in vivo. Cryo-electron microscopy reveals that scLCDV1-VILP engages IGF1R in a unique manner, inducing changes in IGF1R conformation that led to separation, rather than juxtaposition, of the transmembrane segments and hence inactivation of the receptor. Thus, scLCDV1-VILP is a natural peptide with specific antagonist properties on IGF1R signaling and may provide a new tool to guide development of hormonal analogues to treat cancers or metabolic disorders sensitive to IGF-1 without affecting glucose metabolism. |
External links | Nat Commun / PubMed:36335114 / PubMed Central |
Methods | EM (single particle) |
Resolution | 4.6 Å |
Structure data | EMDB-26306, PDB-7u23: |
Source |
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Keywords | SIGNALING PROTEIN / IGF-1R ectodomain / inhibitor / viral insulin-like peptide / single-chain LCDV-1 |