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

• Published in: eLife 2020-11, Vol.9
• Main Authors: Joseph, Raji E, Amatya, Neha, Fulton, D Bruce, Engen, John R, Wales, Thomas E, Andreotti, Amy
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - chemistry; Adenine - metabolism; Adenine - pharmacology; Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors; Agammaglobulinaemia Tyrosine Kinase - chemistry; Agammaglobulinaemia Tyrosine Kinase - genetics; allostery; B cells; bruton tyrosine kinase; Cancer; Catalytic Domain; Chemotherapy; COVID-19 - metabolism; COVID-19 - prevention & control; COVID-19 - virology; Dasatinib; Dasatinib - chemistry; Dasatinib - metabolism; Dasatinib - pharmacology; drug resistance; Drug therapy; Humans; hydrogen/deuterium exchange mass spectrometry; kinase inhibitor; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - prevention & control; Lymphomas; Models, Molecular; Molecular Structure; Mutation; nuclear magnetic resonance; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacology; Protein Conformation - drug effects; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Proteins; SARS-CoV-2 - physiology; src Homology Domains - genetics; Structural Biology and Molecular Biophysics; Tyrosine
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.60470

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.