Rational steering of insulin binding specificity by intra-chain chemical crosslinking

Scientific Reports
Jitka VikováJiří Jiráček

Abstract

Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormone's B-chain C-terminus for its IR-B specificity.

References

Feb 28, 1989·Biochemical and Biophysical Research Communications·S Seino, G I Bell
Aug 1, 1989·Molecular Endocrinology·D E MollerJ S Flier
Feb 1, 1996·Journal of Molecular Graphics·R KoradiK Wüthrich
Jun 24, 1998·Journal of Molecular Biology·S LudvigsenN C Kaarsholm
Feb 24, 2006·Nature Reviews. Molecular Cell Biology·Cullen M TaniguchiC Ronald Kahn
Oct 24, 2006·Nature Reviews. Molecular Cell Biology·Philip Cohen
Dec 23, 2006·Proteins·Aneerban BhattacharyaGaetano T Montelione
Apr 17, 2007·Journal of Peptide Science : an Official Publication of the European Peptide Society·Lenka ZákováJirí Jirácek
Aug 28, 2007·Chemical Society Reviews·Yu L Angell, Kevin Burgess
Aug 14, 2008·Chemical Reviews·Morten Meldal, Christian Wenzel Tornøe
May 21, 2009·Journal of Peptide Science : an Official Publication of the European Peptide Society·Alexandra Le Chevalier IsaadPaolo Rovero
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jirí JirácekAndrzej M Brzozowski
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Garib N MurshudovAlexei A Vagin
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·S McNicholasM E M Noble
Apr 8, 2011·Angewandte Chemie·Kai Holland-Nell, Morten Meldal
May 11, 2011·Organic Letters·Sampat Ingale, Philip E Dawson
Jun 1, 2011·PloS One·Tine GlendorfThomas Kjeldsen
May 23, 2012·Nature·Herb Brody
May 23, 2012·Nature·Erika Jonietz
Oct 16, 2012·Organic & Biomolecular Chemistry·Jessica H Park, Marcey L Waters
Jan 11, 2013·Nature·John G MentingMichael C Lawrence
Mar 1, 2013·The Journal of Biological Chemistry·Lenka ŽákováAndrzej M Brzozowski
May 18, 2013·Diabetes, Obesity & Metabolism·R HerringD L Russell-Jones
Sep 17, 2013·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Colin W WardMichael C Lawrence
Jan 5, 2014·Cold Spring Harbor Perspectives in Biology·Jérémie BoucherC Ronald Kahn
Aug 6, 2014·Proceedings of the National Academy of Sciences of the United States of America·John G MentingMichael C Lawrence
Oct 8, 2014·Acta Crystallographica. Section D, Biological Crystallography·Lenka ZákováAndrzej M Brzozowski
Mar 4, 2015·Organic & Biomolecular Chemistry·Geoffrey M WilliamsMargaret A Brimble
Mar 12, 2015·Nature Communications·M Zulema CabailW Todd Miller
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

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Citations

Feb 13, 2017·Journal of Computational Chemistry·Hossein Mohammadiarani, Harish Vashisth
Oct 4, 2017·Endocrine Reviews·Antonino BelfioreRiccardo Vigneri
Jan 26, 2017·Journal of Peptide Science : an Official Publication of the European Peptide Society·Jan PíchaJiří Jiráček
Aug 6, 2017·Scientific Reports·Gary G AdamsRichard B Gillis
Sep 3, 2020·PloS One·Pavlo PotalitsynLenka Žáková
Aug 12, 2016·The Journal of Biological Chemistry·Rozálie HexnerováLenka Žáková
Aug 12, 2017·Frontiers in Endocrinology·Jiří Jiráček, Lenka Žáková
Sep 11, 2020·Journal of Labelled Compounds & Radiopharmaceuticals·Jiří JiráčekAleš Marek
Nov 28, 2017·Journal of Medicinal Chemistry·Kateřina MacháčkováJiří Jiráček
Jul 26, 2019·ACS Chemical Biology·Florence M BrunelRichard D DiMarchi
Oct 1, 2021·Journal of Medicinal Chemistry·Terezie PáníkováJiří Jiráček

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