Issue 1, 2021

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

Abstract

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.

Graphical abstract: Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

Supplementary files

Article information

Article type
Edge Article
Submitted
17 Sep 2020
Accepted
30 Okt 2020
First published
02 Nov 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 464-476

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

D. Ni, J. Wei, X. He, A. U. Rehman, X. Li, Y. Qiu, J. Pu, S. Lu and J. Zhang, Chem. Sci., 2021, 12, 464 DOI: 10.1039/D0SC05131D

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements