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Allosteric binding sites in Rab11 for potential drug candidates

Rab11 is an important protein subfamily in the RabGTPase family. These proteins physiologically function as key regulators of intracellular membrane trafficking processes. Pathologically, Rab11 proteins are implicated in many diseases including cancers, neurodegenerative diseases and type 2 diabetes...

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Detalles Bibliográficos
Autores principales: Kumar, Ammu Prasanna, Lukman, Suryani
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991966/
https://www.ncbi.nlm.nih.gov/pubmed/29874286
http://dx.doi.org/10.1371/journal.pone.0198632
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author Kumar, Ammu Prasanna
Lukman, Suryani
author_facet Kumar, Ammu Prasanna
Lukman, Suryani
author_sort Kumar, Ammu Prasanna
collection PubMed
description Rab11 is an important protein subfamily in the RabGTPase family. These proteins physiologically function as key regulators of intracellular membrane trafficking processes. Pathologically, Rab11 proteins are implicated in many diseases including cancers, neurodegenerative diseases and type 2 diabetes. Although they are medically important, no previous study has found Rab11 allosteric binding sites where potential drug candidates can bind to. In this study, by employing multiple clustering approaches integrating principal component analysis, independent component analysis and locally linear embedding, we performed structural analyses of Rab11 and identified eight representative structures. Using these representatives to perform binding site mapping and virtual screening, we identified two novel binding sites in Rab11 and small molecules that can preferentially bind to different conformations of these sites with high affinities. After identifying the binding sites and the residue interaction networks in the representatives, we computationally showed that these binding sites may allosterically regulate Rab11, as these sites communicate with switch 2 region that binds to GTP/GDP. These two allosteric binding sites in Rab11 are also similar to two allosteric pockets in Ras that we discovered previously.
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spelling pubmed-59919662018-06-15 Allosteric binding sites in Rab11 for potential drug candidates Kumar, Ammu Prasanna Lukman, Suryani PLoS One Research Article Rab11 is an important protein subfamily in the RabGTPase family. These proteins physiologically function as key regulators of intracellular membrane trafficking processes. Pathologically, Rab11 proteins are implicated in many diseases including cancers, neurodegenerative diseases and type 2 diabetes. Although they are medically important, no previous study has found Rab11 allosteric binding sites where potential drug candidates can bind to. In this study, by employing multiple clustering approaches integrating principal component analysis, independent component analysis and locally linear embedding, we performed structural analyses of Rab11 and identified eight representative structures. Using these representatives to perform binding site mapping and virtual screening, we identified two novel binding sites in Rab11 and small molecules that can preferentially bind to different conformations of these sites with high affinities. After identifying the binding sites and the residue interaction networks in the representatives, we computationally showed that these binding sites may allosterically regulate Rab11, as these sites communicate with switch 2 region that binds to GTP/GDP. These two allosteric binding sites in Rab11 are also similar to two allosteric pockets in Ras that we discovered previously. Public Library of Science 2018-06-06 /pmc/articles/PMC5991966/ /pubmed/29874286 http://dx.doi.org/10.1371/journal.pone.0198632 Text en © 2018 Kumar, Lukman http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://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
Kumar, Ammu Prasanna
Lukman, Suryani
Allosteric binding sites in Rab11 for potential drug candidates
title Allosteric binding sites in Rab11 for potential drug candidates
title_full Allosteric binding sites in Rab11 for potential drug candidates
title_fullStr Allosteric binding sites in Rab11 for potential drug candidates
title_full_unstemmed Allosteric binding sites in Rab11 for potential drug candidates
title_short Allosteric binding sites in Rab11 for potential drug candidates
title_sort allosteric binding sites in rab11 for potential drug candidates
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991966/
https://www.ncbi.nlm.nih.gov/pubmed/29874286
http://dx.doi.org/10.1371/journal.pone.0198632
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