Expanding the druggable space of the LSD1/CoREST epigenetic target: New potential binding regions for drug-like molecules, peptides, protein partners, and chromatin

Robertson, James C., Hurley, Nate C., Tortorici, Marcello, Ciossani, Giuseppe, Borrello, Maria Teresa, Vellore, Nadeem A., Ganesan, A. ORCID: https://orcid.org/0000-0003-4862-7999, Mattevi, Andrea and Baron, Riccardo (2013) Expanding the druggable space of the LSD1/CoREST epigenetic target: New potential binding regions for drug-like molecules, peptides, protein partners, and chromatin. PLoS Computational Biology, 9 (7). ISSN 1553-7358

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Abstract

Lysine specific demethylase-1 (LSD1/KDM1A) in complex with its corepressor protein CoREST is a promising target for epigenetic drugs. No therapeutic that targets LSD1/CoREST, however, has been reported to date. Recently, extended molecular dynamics (MD) simulations indicated that LSD1/CoREST nanoscale clamp dynamics is regulated by substrate binding and highlighted key hinge points of this large-scale motion as well as the relevance of local residue dynamics. Prompted by the urgent need for new molecular probes and inhibitors to understand LSD1/CoREST interactions with small-molecules, peptides, protein partners, and chromatin, we undertake here a configurational ensemble approach to expand LSD1/CoREST druggability. The independent algorithms FTMap and SiteMap and our newly developed Druggable Site Visualizer (DSV) software tool were used to predict and inspect favorable binding sites. We find that the hinge points revealed by MD simulations at the SANT2/Tower interface, at the SWIRM/AOD interface, and at the AOD/Tower interface are new targets for the discovery of molecular probes to block association of LSD1/CoREST with chromatin or protein partners. A fourth region was also predicted from simulated configurational ensembles and was experimentally validated to have strong binding propensity. The observation that this prediction would be prevented when using only the X-ray structures available (including the X-ray structure bound to the same peptide) underscores the relevance of protein dynamics in protein interactions. A fifth region was highlighted corresponding to a small pocket on the AOD domain. This study sets the basis for future virtual screening campaigns targeting the five novel regions reported herein and for the design of LSD1/CoREST mutants to probe LSD1/CoREST binding with chromatin and various protein partners.

Item Type:	Article
Additional Information:	© 2013 Robertson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Faculty \ School:	Faculty of Science > School of Pharmacy Faculty of Science
UEA Research Groups:	Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017) Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Depositing User:	Pure Connector
Date Deposited:	11 Jun 2014 13:04
Last Modified:	24 Oct 2022 06:19
URI:	https://ueaeprints.uea.ac.uk/id/eprint/48566
DOI:	10.1371/journal.pcbi.1003158

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