7U23

Single-chain LCDV-1 viral insulin-like peptide bound to IGF-1R ectodomain, leucine-zippered form

Summary for 7U23

• Entry DOI: 10.2210/pdb7u23/pdb
• EMDB information: 26306
• Descriptor: Insulin-like growth factor 1 receptor, single-chain LCDV-1 viral insulin-like peptide (2 entities in total)
• Functional Keywords: igf-1r ectodomain, inhibitor, viral insulin-like peptide, single-chain lcdv-1, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 231327.90

Authors

Kirk, N.S.,Lawrence, M.C. (deposition date: 2022-02-22, release date: 2022-11-16, Last modification date: 2025-06-04)

Primary citation

Moreau, F.,Kirk, N.S.,Zhang, F.,Gelfanov, V.,List, E.O.,Chrudinova, M.,Venugopal, H.,Lawrence, M.C.,Jimenez, V.,Bosch, F.,Kopchick, J.J.,DiMarchi, R.D.,Altindis, E.,Ronald Kahn, C.
Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist.
Nat Commun, 13:6700-6700, 2022

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-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.

PubMed: 36335114
DOI: 10.1038/s41467-022-34391-6

Experimental method

ELECTRON MICROSCOPY (4.6 Å)