Structural Complementarity of Bruton's Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases

Bruton's tyrosine kinase (BTK) is a critical component in B-cell receptor (BCR) signaling and is also expressed in haematogenic and innate immune cells. Inhibition of BTK hyperactivity is implicated in B-cell malignancies and autoimmune diseases. This review derives the structural complementarity of the BTK-kinase domain and its inhibitors from recent three-dimensional structures of inhibitor-bound BTK in the protein data bank (PDB). Additionally, this review analyzes BTK-mediated effector responses of B-cell development and antibody production. Covalent inhibitors contain an alpha, beta-unsaturated carbonyl moiety that forms a covalent bond with Cys481, stabilizing alpha C-helix in inactive-out conformation which inhibits Tyr551 autophosphorylation. Asn484, located two carbons far from Cys481, influences the stability of the BTK-transition complex. Non-covalent inhibitors engage the BTK-kinase domain through an induced-fit mechanism independent of Cys481 interaction and bind to Tyr551 in the activation kink resulting in H3 cleft, determining BTK selectivity. Covalent and non-covalent binding to the kinase domain of BTK shall induce conformational changes in other domains; therefore, investigating the whole-length BTK conformation is necessary to comprehend BTK's autophosphorylation inhibition. Knowledge about the structural complementarity of BTK and its inhibitors supports the optimization of existing drugs and the discovery of drugs for implication in B-cell malignancies and autoimmune diseases.

Automated summary

BTK plays a crucial role in B-cell receptor signaling and is involved in B-cell malignancies and autoimmune diseases. This review examines the structural compatibility between BTK-kinase domain and its inhibitors based on recent inhibitor-bound BTK structures in the protein data bank. The study also investigates the effects of BTK on B-cell development and antibody production. Covalent inhibitors stabilize the inactive conformation of BTK by forming a bond with Cys481, while non-covalent inhibitors bind to Tyr551 in the activation kink to determine BTK selectivity. Understanding the structural complementarity of BTK and its inhibitors can aid in drug optimization and the development of therapies for B-cell malignancies and autoimmune diseases.