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Xiong, X.* ; Blakely, A.* ; Kim, J.H.* ; Menting, J.G.* ; Schäfer, I.B.* ; Schubert, H.L.* ; Agrawal, R.* ; Gutmann, T. ; Delaine, C.* ; Zhang, Y.W.* ; Olay Artik, G. ; Merriman, A.* ; Eckert, D.* ; Lawrence, M.C.* ; Coskun, Ü. ; Fisher, S.J.* ; Forbes, B.E.* ; Safavi-Hemami, H.* ; Hill, C.P.* ; Chou, D.H.C.*

Symmetric and asymmetric receptor conformation continuum induced by a new insulin.

Nat. Chem. Biol. 18, 511-519 (2022)
Postprint DOI PMC
Open Access Green
Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions. [Figure not available: see fulltext.]
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 1552-4450
e-ISSN 1552-4469
Journal Nature Chemical Biology
Quellenangaben Volume: 18, Issue: 5, Pages: 511-519 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Basingstoke
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute for Pancreatic Beta Cell Research (IPI)