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Conformational Dynamics of Insulin
We have exploited a prandial insulin analog to elucidate the underlying structure and dynamics of insulin as a monomer in solution. A model was provided by insulin lispro (the active component of Humalog(®); Eli Lilly and Co.). Whereas NMR-based modeling recapitulated structural relationships of ins...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Research Foundation
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355934/ https://www.ncbi.nlm.nih.gov/pubmed/22649374 http://dx.doi.org/10.3389/fendo.2011.00048 |
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author | Hua, Qing-Xin Jia, Wenhua Weiss, Michael A. |
author_facet | Hua, Qing-Xin Jia, Wenhua Weiss, Michael A. |
author_sort | Hua, Qing-Xin |
collection | PubMed |
description | We have exploited a prandial insulin analog to elucidate the underlying structure and dynamics of insulin as a monomer in solution. A model was provided by insulin lispro (the active component of Humalog(®); Eli Lilly and Co.). Whereas NMR-based modeling recapitulated structural relationships of insulin crystals (T-state protomers), dynamic anomalies were revealed by amide-proton exchange kinetics in D(2)O. Surprisingly, the majority of hydrogen bonds observed in crystal structures are only transiently maintained in solution, including key T-state-specific inter-chain contacts. Long-lived hydrogen bonds (as defined by global exchange kinetics) exist only at a subset of four α-helical sites (two per chain) flanking an internal disulfide bridge (cystine A20–B19); these sites map within the proposed folding nucleus of proinsulin. The anomalous flexibility of insulin otherwise spans its active surface and may facilitate receptor binding. Because conformational fluctuations promote the degradation of pharmaceutical formulations, we envisage that “dynamic re-engineering” of insulin may enable design of ultra-stable formulations for humanitarian use in the developing world. |
format | Online Article Text |
id | pubmed-3355934 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Frontiers Research Foundation |
record_format | MEDLINE/PubMed |
spelling | pubmed-33559342012-05-30 Conformational Dynamics of Insulin Hua, Qing-Xin Jia, Wenhua Weiss, Michael A. Front Endocrinol (Lausanne) Endocrinology We have exploited a prandial insulin analog to elucidate the underlying structure and dynamics of insulin as a monomer in solution. A model was provided by insulin lispro (the active component of Humalog(®); Eli Lilly and Co.). Whereas NMR-based modeling recapitulated structural relationships of insulin crystals (T-state protomers), dynamic anomalies were revealed by amide-proton exchange kinetics in D(2)O. Surprisingly, the majority of hydrogen bonds observed in crystal structures are only transiently maintained in solution, including key T-state-specific inter-chain contacts. Long-lived hydrogen bonds (as defined by global exchange kinetics) exist only at a subset of four α-helical sites (two per chain) flanking an internal disulfide bridge (cystine A20–B19); these sites map within the proposed folding nucleus of proinsulin. The anomalous flexibility of insulin otherwise spans its active surface and may facilitate receptor binding. Because conformational fluctuations promote the degradation of pharmaceutical formulations, we envisage that “dynamic re-engineering” of insulin may enable design of ultra-stable formulations for humanitarian use in the developing world. Frontiers Research Foundation 2011-10-18 /pmc/articles/PMC3355934/ /pubmed/22649374 http://dx.doi.org/10.3389/fendo.2011.00048 Text en Copyright © 2011 Hua, Jia and Weiss. http://www.frontiersin.org/licenseagreement This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with. |
spellingShingle | Endocrinology Hua, Qing-Xin Jia, Wenhua Weiss, Michael A. Conformational Dynamics of Insulin |
title | Conformational Dynamics of Insulin |
title_full | Conformational Dynamics of Insulin |
title_fullStr | Conformational Dynamics of Insulin |
title_full_unstemmed | Conformational Dynamics of Insulin |
title_short | Conformational Dynamics of Insulin |
title_sort | conformational dynamics of insulin |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355934/ https://www.ncbi.nlm.nih.gov/pubmed/22649374 http://dx.doi.org/10.3389/fendo.2011.00048 |
work_keys_str_mv | AT huaqingxin conformationaldynamicsofinsulin AT jiawenhua conformationaldynamicsofinsulin AT weissmichaela conformationaldynamicsofinsulin |