Cargando…
Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy
Allostery, which is one of the most direct and efficient methods to fine-tune protein functions, has gained increasing recognition in drug discovery. However, there are several challenges associated with the identification of allosteric sites, which is the fundamental cornerstone of drug design. Pre...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178949/ https://www.ncbi.nlm.nih.gov/pubmed/34163609 http://dx.doi.org/10.1039/d0sc05131d |
_version_ | 1783703678798004224 |
---|---|
author | Ni, Duan Wei, Jiacheng He, Xinheng Rehman, Ashfaq Ur Li, Xinyi Qiu, Yuran Pu, Jun Lu, Shaoyong Zhang, Jian |
author_facet | Ni, Duan Wei, Jiacheng He, Xinheng Rehman, Ashfaq Ur Li, Xinyi Qiu, Yuran Pu, Jun Lu, Shaoyong Zhang, Jian |
author_sort | Ni, Duan |
collection | PubMed |
description | Allostery, which is one of the most direct and efficient methods to fine-tune protein functions, has gained increasing recognition in drug discovery. However, there are several challenges associated with the identification of allosteric sites, which is the fundamental cornerstone of drug design. Previous studies on allosteric site predictions have focused on communication signals propagating from the allosteric sites to the orthosteric sites. However, recent biochemical studies have revealed that allosteric coupling is bidirectional and that orthosteric perturbations can modulate allosteric sites through reversed allosteric communication. Here, we proposed a new framework for the prediction of allosteric sites based on reversed allosteric communication using a combination of computational and experimental strategies (molecular dynamics simulations, Markov state models, and site-directed mutagenesis). The desirable performance of our approach was demonstrated by predicting the known allosteric site of the small molecule MDL-801 in nicotinamide dinucleotide (NAD(+))-dependent protein lysine deacetylase sirtuin 6 (Sirt6). A potential novel cryptic allosteric site located around the L116, R119, and S120 residues within the dynamic ensemble of Sirt6 was identified. The allosteric effect of the predicted site was further quantified and validated using both computational and experimental approaches. This study proposed a state-of-the-art computational pipeline for detecting allosteric sites based on reversed allosteric communication. This method enabled the identification of a previously uncharacterized potential cryptic allosteric site on Sirt6, which provides a starting point for allosteric drug design that can aid the identification of candidate pockets in other therapeutic targets. |
format | Online Article Text |
id | pubmed-8178949 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-81789492021-06-22 Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy Ni, Duan Wei, Jiacheng He, Xinheng Rehman, Ashfaq Ur Li, Xinyi Qiu, Yuran Pu, Jun Lu, Shaoyong Zhang, Jian Chem Sci Chemistry Allostery, which is one of the most direct and efficient methods to fine-tune protein functions, has gained increasing recognition in drug discovery. However, there are several challenges associated with the identification of allosteric sites, which is the fundamental cornerstone of drug design. Previous studies on allosteric site predictions have focused on communication signals propagating from the allosteric sites to the orthosteric sites. However, recent biochemical studies have revealed that allosteric coupling is bidirectional and that orthosteric perturbations can modulate allosteric sites through reversed allosteric communication. Here, we proposed a new framework for the prediction of allosteric sites based on reversed allosteric communication using a combination of computational and experimental strategies (molecular dynamics simulations, Markov state models, and site-directed mutagenesis). The desirable performance of our approach was demonstrated by predicting the known allosteric site of the small molecule MDL-801 in nicotinamide dinucleotide (NAD(+))-dependent protein lysine deacetylase sirtuin 6 (Sirt6). A potential novel cryptic allosteric site located around the L116, R119, and S120 residues within the dynamic ensemble of Sirt6 was identified. The allosteric effect of the predicted site was further quantified and validated using both computational and experimental approaches. This study proposed a state-of-the-art computational pipeline for detecting allosteric sites based on reversed allosteric communication. This method enabled the identification of a previously uncharacterized potential cryptic allosteric site on Sirt6, which provides a starting point for allosteric drug design that can aid the identification of candidate pockets in other therapeutic targets. The Royal Society of Chemistry 2020-11-02 /pmc/articles/PMC8178949/ /pubmed/34163609 http://dx.doi.org/10.1039/d0sc05131d Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Ni, Duan Wei, Jiacheng He, Xinheng Rehman, Ashfaq Ur Li, Xinyi Qiu, Yuran Pu, Jun Lu, Shaoyong Zhang, Jian Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy |
title | Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy |
title_full | Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy |
title_fullStr | Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy |
title_full_unstemmed | Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy |
title_short | Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy |
title_sort | discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178949/ https://www.ncbi.nlm.nih.gov/pubmed/34163609 http://dx.doi.org/10.1039/d0sc05131d |
work_keys_str_mv | AT niduan discoveryofcrypticallostericsitesusingreversedallostericcommunicationbyacombinedcomputationalandexperimentalstrategy AT weijiacheng discoveryofcrypticallostericsitesusingreversedallostericcommunicationbyacombinedcomputationalandexperimentalstrategy AT hexinheng discoveryofcrypticallostericsitesusingreversedallostericcommunicationbyacombinedcomputationalandexperimentalstrategy AT rehmanashfaqur discoveryofcrypticallostericsitesusingreversedallostericcommunicationbyacombinedcomputationalandexperimentalstrategy AT lixinyi discoveryofcrypticallostericsitesusingreversedallostericcommunicationbyacombinedcomputationalandexperimentalstrategy AT qiuyuran discoveryofcrypticallostericsitesusingreversedallostericcommunicationbyacombinedcomputationalandexperimentalstrategy AT pujun discoveryofcrypticallostericsitesusingreversedallostericcommunicationbyacombinedcomputationalandexperimentalstrategy AT lushaoyong discoveryofcrypticallostericsitesusingreversedallostericcommunicationbyacombinedcomputationalandexperimentalstrategy AT zhangjian discoveryofcrypticallostericsitesusingreversedallostericcommunicationbyacombinedcomputationalandexperimentalstrategy |