What question did this study set out to answer?

Investigate the impact of active site inhibitor binding and resistance mutations on the global conformational state and autoinhibition of full-length Bruton's tyrosine kinase.

November 23, 2020eLifeOpen Access

Differential impact of BTK active site inhibitors on the conformational state of full-length BTK

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Authors

RJR JosephIowa State University NANeha AmatyaIowa State University DFD. Bruce FultonIowa State University

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Implication

Structural analysis reveals active site inhibitors shift full-length BTK conformational equilibria, highlighting long-range allosteric consequences for leukemia drug design.

Key Points

Investigate the impact of active site inhibitor binding and resistance mutations on the global conformational state and autoinhibition of full-length Bruton's tyrosine kinase.
Assessed conformational alterations in full-length BTK induced by a panel of kinase active site inhibitors, including the covalent inhibitor ibrutinib.
Characterized the structural consequences of the remote T316A ibrutinib resistance mutation within the BTK SH2 domain.
Active site inhibitors induced diverse, large-scale shifts in the conformational equilibria of the regulatory domains of full-length BTK.
The T316A resistance mutation in the SH2 domain promoted spurious BTK activity by destabilizing the compact autoinhibitory conformation and shifting the ensemble away from the autoinhibited state.

Cite This Study

Joseph et al. (2020) studied this question.

synapsesocial.com/papers/6a17dea30a2f3f8e1412e65c https://doi.org/10.7554/elife.60470

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Implication

Structural analysis reveals active site inhibitors shift full-length BTK conformational equilibria, highlighting long-range allosteric consequences for leukemia drug design.

Differential impact of BTK active site inhibitors on the conformational state of full-length BTK

Discussion

Member takes

Implication

Key Points

Cite This Study

Differential impact of BTK active site inhibitors on the conformational state of full-length BTK

Discussion

Member takes

Implication

Key Points

Cite This Study

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