Panova, S., Cliff, M.J., Macek, P. et al. (6 more authors) (2019) Mapping hidden residual structure within the Myc bHLH-LZ domain using chemical denaturant titration. Structure, 27 (10). 1537-1546.e4. ISSN 0969-2126
Abstract
Intrinsically disordered proteins (IDPs) underpin biological regulation and hence are highly desirable drug-development targets. NMR is normally the tool of choice for studying the conformational preferences of IDPs, but the association of regions with residual structure into partially collapsed states can lead to poor spectral quality. The bHLH-LZ domain of the oncoprotein Myc is an archetypal example of such behavior. To circumvent spectral limitations, we apply chemical denaturant titration (CDT)-NMR, which exploits the predictable manner in which chemical denaturants disrupt residual structure and the rapid exchange between conformers in IDP ensembles. The secondary structure propensities and tertiary interactions of Myc are determined for all bHLH-LZ residues, including those with poor NMR properties under native conditions. This reveals conformations that are not predictable using existing crystal structures. The CDT-NMR method also maps sites perturbed by the prototype Myc inhibitor, 10058-F4, to areas of residual structure.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 Elsevier. This is an author produced version of a paper subsequently published in Structure. Uploaded in accordance with the publisher's self-archiving policy. Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
Keywords: | intrinsically disordered proteins; Myc; guanidinium chloride; molten globule; solution NMR; paramagnetic relaxation enhancement |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Molecular Biology and Biotechnology (Sheffield) |
Funding Information: | Funder Grant number Biotechnology and Biological Sciences Research Council (BBSRC) BBS/B/10218 Lister Institute of Preventative Medicine UNSPECIFIED |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 21 Aug 2019 11:03 |
Last Modified: | 10 Dec 2021 10:27 |
Status: | Published |
Publisher: | Elsevier (Cell Press) |
Refereed: | Yes |
Identification Number: | 10.1016/j.str.2019.07.006 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:149959 |