Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States.
Department of Chemistry and Chemical Biology, Northeastern University, Boston, United States.
Elife. 2020 Nov 23;9:e60470. 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.
布鲁顿酪氨酸激酶（BTK）是治疗 B 细胞疾病（包括白血病和淋巴瘤）的靶点。目前已批准的 BTK 抑制剂，包括伊布替尼，一种 BTK 的首创共价抑制剂，直接结合激酶的活性位点。虽然这些抑制剂能有效抑制 BTK 的催化活性，但药物结合对全长 BTK 整体构象的影响尚不清楚。在这里，我们揭示了一组活性位点抑制剂诱导的全长 BTK 的一系列构象效应，包括调节域构象平衡的大规模转变。此外，我们发现，BTK SH2 结构域中的一个远程伊布替尼耐药突变 T316A 通过破坏全长 BTK 的紧凑自抑制构象，导致 BTK 异常活性，使构象整体偏离自抑制形式。BTK 抑制剂的未来发展需要考虑抑制剂结合的远程变构效应，包括这些 BTK 抑制剂在治疗 COVID-19 中的新应用。
