Symmetric and asymmetric receptor conformation continuum induced by a new insulin

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

Symmetric and asymmetric receptor conformation continuum induced by a new insulin. / Xiong, Xiaochun; Blakely, Alan; Kim, Jin Hwan; Menting, John G.; Schäfer, Ingmar B.; Schubert, Heidi L.; Agrawal, Rahul; Gutmann, Theresia; Delaine, Carlie; Zhang, Yi Wolf; Artik, Gizem Olay; Merriman, Allanah; Eckert, Debbie; Lawrence, Michael C.; Coskun, Ünal; Fisher, Simon J.; Forbes, Briony E.; Safavi-Hemami, Helena; Hill, Christopher P.; Chou, Danny Hung Chieh.

I: Nature Chemical Biology, Bind 18, Nr. 5, 2022, s. 511-519.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

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, bind 18, nr. 5, s. 511-519. https://doi.org/10.1038/s41589-022-00981-0

APA

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

Vancouver

Xiong X, Blakely A, Kim JH, Menting JG, Schäfer IB, Schubert HL o.a. Symmetric and asymmetric receptor conformation continuum induced by a new insulin. Nature Chemical Biology. 2022;18(5):511-519. https://doi.org/10.1038/s41589-022-00981-0

Author

Xiong, Xiaochun ; Blakely, Alan ; Kim, Jin Hwan ; Menting, John G. ; Schäfer, Ingmar B. ; Schubert, Heidi L. ; Agrawal, Rahul ; Gutmann, Theresia ; Delaine, Carlie ; Zhang, Yi Wolf ; Artik, Gizem Olay ; Merriman, Allanah ; Eckert, Debbie ; Lawrence, Michael C. ; Coskun, Ünal ; Fisher, Simon J. ; Forbes, Briony E. ; Safavi-Hemami, Helena ; Hill, Christopher P. ; Chou, Danny Hung Chieh. / Symmetric and asymmetric receptor conformation continuum induced by a new insulin. I: Nature Chemical Biology. 2022 ; Bind 18, Nr. 5. s. 511-519.

Bibtex

@article{c324cbc538c6491fbe9da99c0617ae46,
title = "Symmetric and asymmetric receptor conformation continuum induced by a new insulin",
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.]",
author = "Xiaochun Xiong and Alan Blakely and Kim, {Jin Hwan} and Menting, {John G.} and Sch{\"a}fer, {Ingmar B.} and Schubert, {Heidi L.} and Rahul Agrawal and Theresia Gutmann and Carlie Delaine and Zhang, {Yi Wolf} and Artik, {Gizem Olay} and Allanah Merriman and Debbie Eckert and Lawrence, {Michael C.} and {\"U}nal Coskun and Fisher, {Simon J.} and Forbes, {Briony E.} and Helena Safavi-Hemami and Hill, {Christopher P.} and Chou, {Danny Hung Chieh}",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
doi = "10.1038/s41589-022-00981-0",
language = "English",
volume = "18",
pages = "511--519",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "nature publishing group",
number = "5",

}

RIS

TY - JOUR

T1 - Symmetric and asymmetric receptor conformation continuum induced by a new insulin

AU - Xiong, Xiaochun

AU - Blakely, Alan

AU - Kim, Jin Hwan

AU - Menting, John G.

AU - Schäfer, Ingmar B.

AU - Schubert, Heidi L.

AU - Agrawal, Rahul

AU - Gutmann, Theresia

AU - Delaine, Carlie

AU - Zhang, Yi Wolf

AU - Artik, Gizem Olay

AU - Merriman, Allanah

AU - Eckert, Debbie

AU - Lawrence, Michael C.

AU - Coskun, Ünal

AU - Fisher, Simon J.

AU - Forbes, Briony E.

AU - Safavi-Hemami, Helena

AU - Hill, Christopher P.

AU - Chou, Danny Hung Chieh

N1 - Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022

Y1 - 2022

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.]

U2 - 10.1038/s41589-022-00981-0

DO - 10.1038/s41589-022-00981-0

M3 - Journal article

C2 - 35289328

AN - SCOPUS:85126205351

VL - 18

SP - 511

EP - 519

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 5

ER -

ID: 311340617