Conformational Dynamics of Insulin
We have exploited a prandial insulin analogue (insulin lispro, the active component of Humalog®; Eli Lilly and Co.) to elucidate the underlying structure and dynamics of insulin as a monomer in solution. Whereas NMR-based modeling recapitulates structural relationships of insulin crystals...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2011-10-01
|
| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fendo.2011.00048/full |
| _version_ | 1828364459217780736 |
|---|---|
| author | Qing-xin eHua Wenhua eJai Michael A. Weiss |
| author_facet | Qing-xin eHua Wenhua eJai Michael A. Weiss |
| author_sort | Qing-xin eHua |
| collection | DOAJ |
| description | We have exploited a prandial insulin analogue (insulin lispro, the active component of Humalog®; Eli Lilly and Co.) to elucidate the underlying structure and dynamics of insulin as a monomer in solution. Whereas NMR-based modeling recapitulates structural relationships of insulin crystals (T-state protomers), dynamic anomalies are revealed by amide-proton exchange kinetics in D2O. 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 -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. |
| first_indexed | 2024-04-14T05:15:58Z |
| format | Article |
| id | doaj.art-f7eb3085a0b64bb48777d4da36adfe0d |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-14T05:15:58Z |
| publishDate | 2011-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-f7eb3085a0b64bb48777d4da36adfe0d2022-12-22T02:10:22ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922011-10-01210.3389/fendo.2011.0004814629Conformational Dynamics of InsulinQing-xin eHua0Wenhua eJai1Michael A. Weiss2Case Western Reserve UniversityCase Western Reserve UniversityCase Western Reserve UniversityWe have exploited a prandial insulin analogue (insulin lispro, the active component of Humalog®; Eli Lilly and Co.) to elucidate the underlying structure and dynamics of insulin as a monomer in solution. Whereas NMR-based modeling recapitulates structural relationships of insulin crystals (T-state protomers), dynamic anomalies are revealed by amide-proton exchange kinetics in D2O. 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 -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.http://journal.frontiersin.org/Journal/10.3389/fendo.2011.00048/fullDiabetes MellitusProtein Engineeringprotein structureprotein therapeuticsamide-proton exchangehydrogen bond |
| spellingShingle | Qing-xin eHua Wenhua eJai Michael A. Weiss Conformational Dynamics of Insulin Frontiers in Endocrinology Diabetes Mellitus Protein Engineering protein structure protein therapeutics amide-proton exchange hydrogen bond |
| 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 | Diabetes Mellitus Protein Engineering protein structure protein therapeutics amide-proton exchange hydrogen bond |
| url | http://journal.frontiersin.org/Journal/10.3389/fendo.2011.00048/full |
| work_keys_str_mv | AT qingxinehua conformationaldynamicsofinsulin AT wenhuaejai conformationaldynamicsofinsulin AT michaelaweiss conformationaldynamicsofinsulin |