6HTF

Crystal structure of human Btk SH2 domain bound to rF10 repebody

6HTF の概要

• エントリーDOI: 10.2210/pdb6htf/pdb
• 分子名称: Tyrosine-protein kinase BTK, rF10 repebody (3 entities in total)
• 機能のキーワード: repebody, sh2 domain, btk, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44346.08

構造登録者

Duarte, D.P.,Pojer, F.,Hantschel, O. (登録日: 2018-10-04, 公開日: 2020-05-20, 最終更新日: 2024-11-06)

主引用文献

Duarte, D.P.,Lamontanara, A.J.,La Sala, G.,Jeong, S.,Sohn, Y.K.,Panjkovich, A.,Georgeon, S.,Kukenshoner, T.,Marcaida, M.J.,Pojer, F.,De Vivo, M.,Svergun, D.,Kim, H.S.,Dal Peraro, M.,Hantschel, O.
Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms.
Nat Commun, 11:2319-2319, 2020

PubMed Abstract: Bruton's tyrosine kinase (Btk) is critical for B-cell maturation and activation. Btk loss-of-function mutations cause human X-linked agammaglobulinemia (XLA). In contrast, Btk signaling sustains growth of several B-cell neoplasms which may be treated with tyrosine kinase inhibitors (TKIs). Here, we uncovered the structural mechanism by which certain XLA mutations in the SH2 domain strongly perturb Btk activation. Using a combination of molecular dynamics (MD) simulations and small-angle X-ray scattering (SAXS), we discovered an allosteric interface between the SH2 and kinase domain required for Btk activation and to which multiple XLA mutations map. As allosteric interactions provide unique targeting opportunities, we developed an engineered repebody protein binding to the SH2 domain and able to disrupt the SH2-kinase interaction. The repebody prevents activation of wild-type and TKI-resistant Btk, inhibiting Btk-dependent signaling and proliferation of malignant B-cells. Therefore, the SH2-kinase interface is critical for Btk activation and a targetable site for allosteric inhibition.

PubMed: 32385234
DOI: 10.1038/s41467-020-16128-5

実験手法

X-RAY DIFFRACTION (2.102 Å)