Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation
Over 1000 mutations are described in the androgen receptor (AR) gene. Of those, about 600 were found in androgen insensitivity syndrome (AIS) patients, among which 400 mutations affect the ligand-binding domain (LBD) of the AR protein. Recently, we reported a novel missense mutation c.2507T>G I83...
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MDPI AG
2021-07-01
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| Online Access: | https://www.mdpi.com/2075-1729/11/7/659 |
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| author | Alexey Rayevsky Dmytro Sirokha Dariia Samofalova Dmytro Lozhko Olexandra Gorodna Inga Prokopenko Liudmyla Livshits |
| author_facet | Alexey Rayevsky Dmytro Sirokha Dariia Samofalova Dmytro Lozhko Olexandra Gorodna Inga Prokopenko Liudmyla Livshits |
| author_sort | Alexey Rayevsky |
| collection | DOAJ |
| description | Over 1000 mutations are described in the androgen receptor (AR) gene. Of those, about 600 were found in androgen insensitivity syndrome (AIS) patients, among which 400 mutations affect the ligand-binding domain (LBD) of the AR protein. Recently, we reported a novel missense mutation c.2507T>G I836S (ClinVarID: 974911) in a patient with complete AIS (CAIS) phenotype. In the present study, we applied a set of computational approaches for the structural analysis of the ligand-binding domains in a wild-type and mutant AR to evaluate the functional impact of the novel I836S mutation. We revealed that the novel I836S substitution leads to a shorter existence time of the ligand’s gating tunnel and internal cavity, occurring only in the presence of S836 phosphorylation. Additionally, the analysis of phosphorylation of the 836 mutant residues explained the negative impact on AR homodimerization, since monomer surface changes indirectly impacted the binding site. Our analyses provide evidence that I836S causes disruptions of AR protein functionality and development of CAIS clinical features in patients. |
| first_indexed | 2024-03-10T09:34:52Z |
| format | Article |
| id | doaj.art-efa2ed686d5d4a47952d40e7de7e5ff0 |
| institution | Directory Open Access Journal |
| issn | 2075-1729 |
| language | English |
| last_indexed | 2024-03-10T09:34:52Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Life |
| spelling | doaj.art-efa2ed686d5d4a47952d40e7de7e5ff02023-11-22T04:12:43ZengMDPI AGLife2075-17292021-07-0111765910.3390/life11070659Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S MutationAlexey Rayevsky0Dmytro Sirokha1Dariia Samofalova2Dmytro Lozhko3Olexandra Gorodna4Inga Prokopenko5Liudmyla Livshits6Laboratory of Bioinformatics and Structural Biology, Institute of Food Biotechnology and Genomics, National Academy of Sciences of Ukraine, 04123 Kyiv, UkraineInstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03143 Kyiv, UkraineLaboratory of Bioinformatics and Structural Biology, Institute of Food Biotechnology and Genomics, National Academy of Sciences of Ukraine, 04123 Kyiv, UkraineInstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03143 Kyiv, UkraineInstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03143 Kyiv, UkraineDepartment of Clinical & Experimental Medicine, School of Biosciences & Medicine, University of Surrey, Guildford GU2 7XH, UKInstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03143 Kyiv, UkraineOver 1000 mutations are described in the androgen receptor (AR) gene. Of those, about 600 were found in androgen insensitivity syndrome (AIS) patients, among which 400 mutations affect the ligand-binding domain (LBD) of the AR protein. Recently, we reported a novel missense mutation c.2507T>G I836S (ClinVarID: 974911) in a patient with complete AIS (CAIS) phenotype. In the present study, we applied a set of computational approaches for the structural analysis of the ligand-binding domains in a wild-type and mutant AR to evaluate the functional impact of the novel I836S mutation. We revealed that the novel I836S substitution leads to a shorter existence time of the ligand’s gating tunnel and internal cavity, occurring only in the presence of S836 phosphorylation. Additionally, the analysis of phosphorylation of the 836 mutant residues explained the negative impact on AR homodimerization, since monomer surface changes indirectly impacted the binding site. Our analyses provide evidence that I836S causes disruptions of AR protein functionality and development of CAIS clinical features in patients.https://www.mdpi.com/2075-1729/11/7/659androgen receptorligand-binding domainmutationmolecular modelingmolecular dynamicstime isolated RMSF |
| spellingShingle | Alexey Rayevsky Dmytro Sirokha Dariia Samofalova Dmytro Lozhko Olexandra Gorodna Inga Prokopenko Liudmyla Livshits Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation Life androgen receptor ligand-binding domain mutation molecular modeling molecular dynamics time isolated RMSF |
| title | Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation |
| title_full | Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation |
| title_fullStr | Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation |
| title_full_unstemmed | Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation |
| title_short | Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation |
| title_sort | functional effects in silico prediction for androgen receptor ligand binding domain novel i836s mutation |
| topic | androgen receptor ligand-binding domain mutation molecular modeling molecular dynamics time isolated RMSF |
| url | https://www.mdpi.com/2075-1729/11/7/659 |
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