Najmi Asim, Thangavel Neelaveni, Mohanan Anugeetha Thacheril, Qadri Marwa, Albratty Mohammed, Ashraf Safeena Eranhiyil, Saleh Safaa Fathy, Nayeem Maryam, Mohan Syam
Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia.
Department of Pharmacology, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia.
Pharmaceuticals (Basel). 2023 Mar 7;16(3):400. doi: 10.3390/ph16030400.
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 α, β-unsaturated carbonyl moiety that forms a covalent bond with Cys481, stabilizing αC-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.
布鲁顿酪氨酸激酶（BTK）是B细胞受体（BCR）信号传导中的关键成分，也在造血和先天免疫细胞中表达。抑制BTK的过度活性与B细胞恶性肿瘤和自身免疫性疾病有关。本综述从蛋白质数据库（PDB）中抑制剂结合的BTK的最新三维结构推导BTK激酶结构域与其抑制剂的结构互补性。此外，本综述分析了BTK介导的B细胞发育和抗体产生的效应反应。共价抑制剂含有一个α，β-不饱和羰基部分，该部分与Cys481形成共价键，使αC螺旋稳定在非活性外向构象，从而抑制Tyr551的自磷酸化。位于距Cys481两个碳原子处的Asn484影响BTK过渡复合物的稳定性。非共价抑制剂通过一种不依赖于Cys481相互作用的诱导契合机制与BTK激酶结构域结合，并与激活扭结中的Tyr551结合，导致H3裂隙，从而决定BTK的选择性。与BTK激酶结构域的共价和非共价结合会在其他结构域中诱导构象变化；因此，研究全长BTK构象对于理解BTK的自磷酸化抑制是必要的。关于BTK及其抑制剂的结构互补性的知识支持现有药物的优化以及用于B细胞恶性肿瘤和自身免疫性疾病的药物发现。
