Year: 2022
Type: article
Abstract: 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 a fully active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy and protein engineering to elucidate its interactions with the human insulin receptor ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of native insulin but also compromise therapeutic utility by delaying the onset action, suggesting approaches to develop improved therapeutic insulins. Curiously, a receptor conformation present in low abundance adopts a highly asymmetric structure that displays novel coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions.
Source: Nature Chemical Biology
Authors: Xiaochun Xiong, Alan Blakely, Jin Hwan Kim, John G. Menting, Ingmar B. Schäfer, Heidi L. Schubert, Rahul Agrawal, Theresia Gutmann, Carlie Delaine, Yi Wolf Zhang, Gizem Olay Artik, Allanah Merriman, Debbie Eckert, Michael C. Lawrence, Ünal Coskun, Simon J. Fisher, Briony E. Forbes, Helena Safavi-Hemami, Christopher P. Hill, Danny Hung-Chieh Chou
Institutions: University of Utah, Stanford Medicine, Stanford University, The University of Melbourne, Walter and Eliza Hall Institute of Medical Research, Max Planck Institute of Biochemistry, Helmholtz Munich, Max Planck Institute of Molecular Cell Biology and Genetics, German Center for Diabetes Research, University Hospital Carl Gustav Carus, Paul Langerhans Institute Dresden, Technische Universität Dresden, Flinders University, University of Kentucky, University of Copenhagen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Health and Human Services, University of Utah, Villum Fonden, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: DEVELOPMENT OF CONCENTRATED, STABLE ULTRA FAST-ACTING INSULIN FORMULATION, G2493971080, G3879947821, G5222967801, FOR 2682: Seasonal temperature acclimation in Drosophila, G6429742729, G6600012508, Regulation der zellulären Signaltransduktion durch Lipide der inneren Zellmembran, STUDIES ON INSULIN RECEPTOR ISO FORMS, G8565676200, Pharmacological Approach to the Restoration of Hypoglycemia Awareness, Structural Insights to Insulin Receptor Ligand Interactions
OpenAlex ID: W4221132537