Symmetric and asymmetric receptor conformation continuum induced by a new insulin

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

doi:10.1038/s41589-022-00981-0

Symmetric and asymmetric receptor conformation continuum induced by a new insulin

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

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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 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.]

Original language	English
Pages (from-to)	511-519
Number of pages	9
Journal	Nature Chemical Biology
Volume	18
Issue number	5
DOIs	https://doi.org/10.1038/s41589-022-00981-0
State	Published - May 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

We thank B.M. Olivera for cone snail collection and identification and insightful discussions, P. Shen for advice with structure determination and editing, D. Timm for EM screening and data collection at the University of Utah Electron Microscopy Core Laboratory and Paula Flórez Salcedo for the illustration of the Conus kinoshitai shell. The support and resources from the Center for High Performance Computing and the High Throughput Genomics Core Facility at the University of Utah are gratefully acknowledged. Financial support was provided by the National Institutes of Health NIDDK (DK120430 to D.H.-C.C., DK127268 to C.P.H. and DK118082 to S.J.F.), NIGMS (GM125001 to D.H.-C.C.), Juvenile Diabetes Research Foundation (5-CDA-2018-572-A-N to D.H.-C.C. and 1-INO-2017-441-A-N to H.S.-H.), German Federal Ministry of Education and Research (BMBF) grant to the German Center for Diabetes Research (DZD e.V. to Ü.C.), Deutsche Forschungsgemeinschaft (DFG 251981924–TRR 83 to Ü.C. and DFG 347368302 to Ü.C. and T.G.) and the Australian National Health and Medical Research Council (APP1143546 to M.C.L. and B.E.F.). Support of M.C.L.’s research is also made possible at WEHI through Victorian State Government Operational Infrastructure Support and the Australian NHMRC Independent Research Institutes Infrastructure Support Scheme. H.S.-H. acknowledges fellowship support from the Villum Foundation (19063) and the Carlsberg Foundation (CF19-0445).

Funders	Funder number
Bundesministerium für Bildung und Forschung
National Institutes of Health (NIH)
University of Utah
German Center for Diabetes Research
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK118082, R01DK127268, R01DK120430
Villum Fonden	19063
Australian National Health and Medical Research Council	1143546, APP1143546
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	R35GM125001
Carlsbergfondet	CF19-0445
Juvenile Diabetes Research Foundation International	5-CDA-2018-572-A-N, 1-INO-2017-441-A-N
Deutsche Forschungsgemeinschaft	DFG 347368302, DFG 251981924–TRR 83

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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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., Artik, G. O., 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. (2022). Symmetric and asymmetric receptor conformation continuum induced by a new insulin. Nature Chemical Biology, 18(5), 511-519. https://doi.org/10.1038/s41589-022-00981-0

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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 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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Xiong, X, Blakely, A, Kim, JH, Menting, JG, Schäfer, IB, Schubert, HL, Agrawal, R, Gutmann, T, Delaine, C, Zhang, YW, Artik, GO, Merriman, A, Eckert, D, Lawrence, MC, Coskun, Ü, Fisher, SJ, Forbes, BE, Safavi-Hemami, H, Hill, CP & Chou, DHC 2022, 'Symmetric and asymmetric receptor conformation continuum induced by a new insulin', Nature Chemical Biology, vol. 18, no. 5, pp. 511-519. https://doi.org/10.1038/s41589-022-00981-0

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N2 - 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.]

AB - 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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Symmetric and asymmetric receptor conformation continuum induced by a new insulin

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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