Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan; Laboratory for Computational and Structural Biology, Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala 680005, India.
Laboratory for Protein Functional and Structural Biology, Center for Biosystems Dynamics Research, RIKEN, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan; Drug Discovery Structural Biology Platform Unit, Center for Biosystems Dynamics Research, RIKEN, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
Int J Biol Macromol. 2022 Jun 15;210:172-181. doi: 10.1016/j.ijbiomac.2022.05.009. Epub 2022 May 6.
Alzheimer's disease (AD) is one of the most common, progressive neurodegenerative disorders affecting the aged populations. Though various disease pathologies have been suggested for AD, the impairment of the cholinergic system is one of the critical factors for the disease progression. Restoration of the cholinergic transmission through acetylcholinesterase (AChE) inhibitors is a promising disease modifying therapy. Being the first marketed drug for AD, tacrine reversibly inhibits AChE and thereby slows the breakdown of the chemical messenger acetylcholine (ACh) in the brain. However, the atomic level of interactions of tacrine towards human AChE (hAChE) is unknown for years. Hence, in the current study, we report the X-ray structure of hAChE-tacrine complex at 2.85 Å resolution. The conformational heterogeneity of tacrine within the electron density was addressed with the help of molecular mechanics assisted methods and the low-energy ligand configuration is reported, which provides a mechanistic explanation for the high binding affinity of tacrine towards AChE. Additionally, structural comparison of reported hAChE structures sheds light on the conformational selection and induced fit effects of various active site residues upon binding to different ligands and provides insight for future drug design campaigns against AD where AChE is a drug target.
阿尔茨海默病（AD）是最常见的进行性神经退行性疾病之一，影响老年人群。尽管已经提出了各种疾病病理学来解释 AD，但胆碱能系统的损伤是疾病进展的关键因素之一。通过乙酰胆碱酯酶（AChE）抑制剂恢复胆碱能传递是一种很有前途的疾病修饰治疗方法。他克林作为 AD 的第一种上市药物，可逆地抑制 AChE，从而减缓大脑中化学信使乙酰胆碱（ACh）的分解。然而，多年来，他克林与人类乙酰胆碱酯酶（hAChE）相互作用的原子水平尚不清楚。因此，在当前的研究中，我们报告了 hAChE-他克林复合物在 2.85Å分辨率下的 X 射线结构。借助分子力学辅助方法解决了他克林在电子密度中的构象异质性问题，并报告了低能量配体构型，这为他克林对 AChE 高结合亲和力提供了机制解释。此外，对报道的 hAChE 结构的结构比较阐明了不同活性位点残基在与不同配体结合时的构象选择和诱导契合效应，并为未来针对 AD 的药物设计活动提供了见解，其中 AChE 是药物靶点。
