Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound Microreceptor
Insulin binding to the insulin receptor (IR) is the first key step in initiating downstream signaling cascades for glucose homeostasis in higher organisms. The molecular details of insulin recognition by IR are not yet completely understood, but a picture of hormone/receptor interactions at one of t...
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| Format: | Article |
| Language: | English |
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MDPI AG
2014-10-01
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| Series: | Membranes |
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| Online Access: | http://www.mdpi.com/2077-0375/4/4/730 |
| _version_ | 1797715281542381568 |
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| author | Harish Vashisth |
| author_facet | Harish Vashisth |
| author_sort | Harish Vashisth |
| collection | DOAJ |
| description | Insulin binding to the insulin receptor (IR) is the first key step in initiating downstream signaling cascades for glucose homeostasis in higher organisms. The molecular details of insulin recognition by IR are not yet completely understood, but a picture of hormone/receptor interactions at one of the epitopes (Site 1) is beginning to emerge from recent structural evidence. However, insulin-bound structures of truncated IR suggest that crystallographic conformation of insulin cannot be accommodated in the full IR ectodomain due to steric overlap of insulin with the first two type III fibronectin domains (F1 and F2), which are contributed to the insulin binding-pocket by the second subunit in the IR homodimer. A conformational change in the F1-F2 pair has thus been suggested. In this work, we present an all-atom structural model of complex of insulin and the IR ectodomain, where no structural overlap of insulin with the receptor domains (F1 and F2) is observed. This structural model was arrived at by flexibly fitting parts of our earlier insulin/IR all-atom model into the simulated density maps of crystallized constructs combined with conformational sampling from apo-IR solution conformations. Importantly, our experimentally-consistent model helps rationalize yet unresolved Site |
| first_indexed | 2024-03-12T08:04:59Z |
| format | Article |
| id | doaj.art-7cc0cccac3614d1cbdefa84b656e991e |
| institution | Directory Open Access Journal |
| issn | 2077-0375 |
| language | English |
| last_indexed | 2024-03-12T08:04:59Z |
| publishDate | 2014-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Membranes |
| spelling | doaj.art-7cc0cccac3614d1cbdefa84b656e991e2023-09-02T19:39:21ZengMDPI AGMembranes2077-03752014-10-014473074610.3390/membranes4040730membranes4040730Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound MicroreceptorHarish Vashisth0Department of Chemical Engineering, University of New Hampshire, 33 Academic Way, Durham,NH 03824, USAInsulin binding to the insulin receptor (IR) is the first key step in initiating downstream signaling cascades for glucose homeostasis in higher organisms. The molecular details of insulin recognition by IR are not yet completely understood, but a picture of hormone/receptor interactions at one of the epitopes (Site 1) is beginning to emerge from recent structural evidence. However, insulin-bound structures of truncated IR suggest that crystallographic conformation of insulin cannot be accommodated in the full IR ectodomain due to steric overlap of insulin with the first two type III fibronectin domains (F1 and F2), which are contributed to the insulin binding-pocket by the second subunit in the IR homodimer. A conformational change in the F1-F2 pair has thus been suggested. In this work, we present an all-atom structural model of complex of insulin and the IR ectodomain, where no structural overlap of insulin with the receptor domains (F1 and F2) is observed. This structural model was arrived at by flexibly fitting parts of our earlier insulin/IR all-atom model into the simulated density maps of crystallized constructs combined with conformational sampling from apo-IR solution conformations. Importantly, our experimentally-consistent model helps rationalize yet unresolved Sitehttp://www.mdpi.com/2077-0375/4/4/730insulininsulin receptorreceptor tyrosine kinasesmembrane receptorsdockingmolecular dynamics simulationssignal transduction |
| spellingShingle | Harish Vashisth Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound Microreceptor Membranes insulin insulin receptor receptor tyrosine kinases membrane receptors docking molecular dynamics simulations signal transduction |
| title | Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound Microreceptor |
| title_full | Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound Microreceptor |
| title_fullStr | Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound Microreceptor |
| title_full_unstemmed | Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound Microreceptor |
| title_short | Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound Microreceptor |
| title_sort | flexibility in the insulin receptor ectodomain enables docking of insulin in crystallographic conformation observed in a hormone bound microreceptor |
| topic | insulin insulin receptor receptor tyrosine kinases membrane receptors docking molecular dynamics simulations signal transduction |
| url | http://www.mdpi.com/2077-0375/4/4/730 |
| work_keys_str_mv | AT harishvashisth flexibilityintheinsulinreceptorectodomainenablesdockingofinsulinincrystallographicconformationobservedinahormoneboundmicroreceptor |