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Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders
Three-dimensional structures of proteins can provide important clues into the efficacy of personalized treatment. We perform a structural analysis of variants within three inherited lysosomal storage disorders, comparing variants responsive to pharmacological chaperone treatment to those unresponsiv...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478239/ https://www.ncbi.nlm.nih.gov/pubmed/34529671 http://dx.doi.org/10.1371/journal.pcbi.1009370 |
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author | Woodard, Jaie Zheng, Wei Zhang, Yang |
author_facet | Woodard, Jaie Zheng, Wei Zhang, Yang |
author_sort | Woodard, Jaie |
collection | PubMed |
description | Three-dimensional structures of proteins can provide important clues into the efficacy of personalized treatment. We perform a structural analysis of variants within three inherited lysosomal storage disorders, comparing variants responsive to pharmacological chaperone treatment to those unresponsive to such treatment. We find that predicted ΔΔG of mutation is higher on average for variants unresponsive to treatment, in the case of datasets for both Fabry disease and Pompe disease, in line with previous findings. Using both a single decision tree and an advanced machine learning approach based on the larger Fabry dataset, we correctly predict responsiveness of three Gaucher disease variants, and we provide predictions for untested variants. Many variants are predicted to be responsive to treatment, suggesting that drug-based treatments may be effective for a number of variants in Gaucher disease. In our analysis, we observe dependence on a topological feature reporting on contact arrangements which is likely connected to the order of folding of protein residues, and we provide a potential justification for this observation based on steady-state cellular kinetics. |
format | Online Article Text |
id | pubmed-8478239 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-84782392021-09-29 Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders Woodard, Jaie Zheng, Wei Zhang, Yang PLoS Comput Biol Research Article Three-dimensional structures of proteins can provide important clues into the efficacy of personalized treatment. We perform a structural analysis of variants within three inherited lysosomal storage disorders, comparing variants responsive to pharmacological chaperone treatment to those unresponsive to such treatment. We find that predicted ΔΔG of mutation is higher on average for variants unresponsive to treatment, in the case of datasets for both Fabry disease and Pompe disease, in line with previous findings. Using both a single decision tree and an advanced machine learning approach based on the larger Fabry dataset, we correctly predict responsiveness of three Gaucher disease variants, and we provide predictions for untested variants. Many variants are predicted to be responsive to treatment, suggesting that drug-based treatments may be effective for a number of variants in Gaucher disease. In our analysis, we observe dependence on a topological feature reporting on contact arrangements which is likely connected to the order of folding of protein residues, and we provide a potential justification for this observation based on steady-state cellular kinetics. Public Library of Science 2021-09-16 /pmc/articles/PMC8478239/ /pubmed/34529671 http://dx.doi.org/10.1371/journal.pcbi.1009370 Text en © 2021 Woodard et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Woodard, Jaie Zheng, Wei Zhang, Yang Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders |
title | Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders |
title_full | Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders |
title_fullStr | Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders |
title_full_unstemmed | Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders |
title_short | Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders |
title_sort | protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478239/ https://www.ncbi.nlm.nih.gov/pubmed/34529671 http://dx.doi.org/10.1371/journal.pcbi.1009370 |
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