Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Protein J. 2022 Apr;41(2):201-215. doi: 10.1007/s10930-022-10046-9. Epub 2022 Mar 2.
B-cell lymphoma 2 (Bcl2) is a key protein regulator of apoptosis. The hydrophobic groove in Bcl2 is a unique structural feature to this class of enzymes and found to have a profound impact on protein overall structure, function, and dynamics. Dynamics of the hydrophobic groove is an essential determinant of the catalytic activity of Bcl2, an implicated protein in Waldenström macroglobulinemia (WM). The mobility of α3-α4 helices around the catalytic site of the protein remains crucial to its activity. The preferential binding mechanisms of the multi-catalytic sites of the Bcl2 enzyme have been a subject of debate in the literature. In addition to our previous report on the same protein, herein, we further investigate the preferential binding modes and the conformational implications of Venetoclax-JQ1 dual drug binding at both catalytic active sites of Bcl2. Structural analysis revealed asymmetric α3-α4 helices movement with the expansion of the distance between the α3 and α4 helix in Venetoclax-JQ1 dual inhibition by 15.2% and 26.3%, respectively when compared to JQ1 and Venetoclax individual drug inhibition-resulting in remarkable widening of hydrophobic groove. Moreso, a reciprocal enhanced binding effect was observed: Venetoclax increased the binding affinity of JQ1 by 11.5%, while the JQ1 fostered the binding affinity of Venetoclax by 16.3% compared with individual inhibition of each drug. This divergence has also resulted in higher protein stability, and prominent correlated motions were observed with the least fluctuations and multiple van der Waals interactions. Findings offer vital conformational dynamics and structural mechanisms of enzyme-single ligand and enzyme-dual ligand interactions, which could potentially shift the current therapeutic protocol of Waldenström macroglobulinemia.
B 细胞淋巴瘤 2（Bcl2）是细胞凋亡的关键蛋白调节因子。Bcl2 的疏水性凹槽是此类酶的独特结构特征，对蛋白质的整体结构、功能和动力学有深远的影响。疏水性凹槽的动力学是 Bcl2 催化活性的重要决定因素，Bcl2 是瓦尔登斯特伦巨球蛋白血症（WM）中的一种有牵连的蛋白。α3-α4 螺旋在蛋白质催化部位周围的移动性对其活性仍然至关重要。Bcl2 酶的多催化位点的优先结合机制一直是文献中的一个争论点。除了我们之前对同一蛋白质的报告，在此，我们进一步研究了 Venetoclax-JQ1 双重药物在 Bcl2 的两个催化活性部位的优先结合模式和构象影响。结构分析显示，不对称的α3-α4 螺旋运动，与 Venetoclax-JQ1 双重抑制相比，α3 和α4 螺旋之间的距离分别扩展了 15.2%和 26.3%，导致疏水性凹槽明显变宽。更重要的是，观察到了相互增强的结合效应：与单独抑制每种药物相比，Venetoclax 增加了 JQ1 的结合亲和力 11.5%，而 JQ1 促进了 Venetoclax 的结合亲和力 16.3%。这种分歧也导致了更高的蛋白质稳定性，并观察到明显的相关运动，波动最小，并有多个范德华相互作用。研究结果提供了酶-单配体和酶-双配体相互作用的重要构象动力学和结构机制，这可能会改变目前瓦尔登斯特伦巨球蛋白血症的治疗方案。
