A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information
The insulin receptor (IR), the insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor-related receptor (IRR) are covalently-linked homodimers made up of several structural domains. The molecular mechanism of ligand binding to the ectodomain of these receptors and the resulting activa...
| Main Authors: | , , , , |
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| Format: | Journal Article |
| Published: |
Public Library of Science (PLoS)
2008
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| Online Access: | http://hdl.handle.net/20.500.11937/29028 |
| _version_ | 1848752693440413696 |
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| author | Renteria, Miguel Gandhi, Neha Vinuesa, P. Helmerhorst, Erik Mancera, Ricardo |
| author_facet | Renteria, Miguel Gandhi, Neha Vinuesa, P. Helmerhorst, Erik Mancera, Ricardo |
| author_sort | Renteria, Miguel |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | The insulin receptor (IR), the insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor-related receptor (IRR) are covalently-linked homodimers made up of several structural domains. The molecular mechanism of ligand binding to the ectodomain of these receptors and the resulting activation of their tyrosine kinase domain is still not well understood. We have carried out an amino acid residue conservation analysis in order to reconstruct the phylogeny of the IR Family. We have confirmed the location of ligand binding site 1 of the IGF1R and IR. Importantly, we have also predicted the likely location of the insulin binding site 2 on the surface of the fibronectin type III domains of the IR. An evolutionary conserved surface on the second leucine-rich domain that may interact with the ligand could not be detected. We suggest a possible mechanical trigger of the activation of the IR that involves a slight 'twist' rotation of the last two fibronectin type III domains in order to face the likely location of insulin. Finally, a strong selective pressure was found amongst the IRR orthologous sequences, suggesting that this orphan receptor has a yet unknown physiological role which may be conserved from amphibians to mammals. |
| first_indexed | 2025-11-14T08:12:41Z |
| format | Journal Article |
| id | curtin-20.500.11937-29028 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T08:12:41Z |
| publishDate | 2008 |
| publisher | Public Library of Science (PLoS) |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-290282017-09-13T15:55:37Z A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information Renteria, Miguel Gandhi, Neha Vinuesa, P. Helmerhorst, Erik Mancera, Ricardo The insulin receptor (IR), the insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor-related receptor (IRR) are covalently-linked homodimers made up of several structural domains. The molecular mechanism of ligand binding to the ectodomain of these receptors and the resulting activation of their tyrosine kinase domain is still not well understood. We have carried out an amino acid residue conservation analysis in order to reconstruct the phylogeny of the IR Family. We have confirmed the location of ligand binding site 1 of the IGF1R and IR. Importantly, we have also predicted the likely location of the insulin binding site 2 on the surface of the fibronectin type III domains of the IR. An evolutionary conserved surface on the second leucine-rich domain that may interact with the ligand could not be detected. We suggest a possible mechanical trigger of the activation of the IR that involves a slight 'twist' rotation of the last two fibronectin type III domains in order to face the likely location of insulin. Finally, a strong selective pressure was found amongst the IRR orthologous sequences, suggesting that this orphan receptor has a yet unknown physiological role which may be conserved from amphibians to mammals. 2008 Journal Article http://hdl.handle.net/20.500.11937/29028 10.1371/journal.pone.0003667 Public Library of Science (PLoS) fulltext |
| spellingShingle | Renteria, Miguel Gandhi, Neha Vinuesa, P. Helmerhorst, Erik Mancera, Ricardo A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information |
| title | A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information |
| title_full | A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information |
| title_fullStr | A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information |
| title_full_unstemmed | A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information |
| title_short | A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information |
| title_sort | comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information |
| url | http://hdl.handle.net/20.500.11937/29028 |