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Lookup NU author(s): Shangze Xu, Lanyu Fan, Dr Piotr Zaborniak, Dr Ruidi Zhu, Haoyuan Ji, Dr Joao Victor De Souza Cunha, Dr Agnieszka Bronowska
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024. Per Arnt Sim domain kinase (PASK) is a conserved metabolic sensor, which modulates the activation of critical proteins involved in liver metabolism and fitness. However, despite its key role in mastering the metabolic regulation, the molecular mechanism of PASK s activity is an ongoing research, and structural information on this important protein is scarce. To investigate this, we integrated structural bioinformatics with state-of-The-Art modelling and molecular simulation techniques. Our goals were to address (1) how many regulatory PAS domains PASK is likely to have, (2) how those domains modulate the kinase activity, and (3) how those interactions could be controlled by small molecules. Our results indicated the existence of three N-Terminal PAS domains. Solvent mapping and fragment docking identified a consensus set of "druggable hot-spots" within all domains, as well as at domain-domain interfaces. Those "hot-spots" could be modulated with chemically diverse small molecular probes, which may serve as a starting point for rationally-designed therapeutics modulating these specific sites. Our results identified a plausible mechanism of auto-inhibition of kinase activity, suggesting that all three putative PAS domains may be required. Future work will focus on validation of the predicted PASK models, and development of small molecule inhibitors of PASK by targeting its "druggable hot-spots".
Author(s): Xu S, Fan L, Zaborniak P, Zhu R, Ji H, Madden KS, De Souza JV, Bronowska AK
Publication type: Article
Publication status: Published
Journal: QRB Discovery
Year: 2024
Pages: Epub ahead of print
Online publication date: 02/02/2024
Acceptance date: 02/04/2018
Date deposited: 19/02/2024
ISSN (electronic): 2633-2892
Publisher: Cambridge University Press
URL: https://doi.org/10.1017/qrd.2024.1
DOI: 10.1017/qrd.2024.1
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