Differential impact of BTK active site inhibitors on the conformational state of full-length BTK
Abstract
Bruton's tyrosine kinase (BTK) is targeted in the treatment of B-cell disorders including leukemias and lymphomas. Currently approved BTK inhibitors, including Ibrutinib, a first-in-class covalent inhibitor of BTK, bind directly to the kinase active site. While effective at blocking the catalytic activity of BTK, consequences of drug binding on the global conformation of full-length BTK are unknown. Here we uncover a range of conformational effects in full-length BTK induced by a panel of active site inhibitors, including large-scale shifts in the conformational equilibria of the regulatory domains. Additionally, we find that a remote Ibrutinib resistance mutation, T316A in the BTK SH2 domain, drives spurious BTK activity by destabilizing the compact autoinhibitory conformation of full-length BTK, shifting the conformational ensemble away from the autoinhibited form. Future development of BTK inhibitors will need to consider long-range allosteric consequences of inhibitor binding, including the emerging application of these BTK inhibitors in treating COVID-19.
Data availability
Hydrogen/deuterium exchange data have been deposited in the PRIDE database.
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BTK regulatory domains escape Ibrutinib inhibitionPRIDE database, PXD020029.
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (AI43957)
- Amy Andreotti
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Joseph et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Structural Biology and Molecular Biophysics
A combination of X-ray crystallography, NMR, and mass spectrometry has revealed how diverse small-molecule inhibitors bind Bruton’s tyrosine kinase and alter the conformation of this enzyme.
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