Carrie L Lomelino, Jacob T Andring, Robert McKenna
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引用次数: 0
摘要
X 射线和中子晶体学是研究生物分子结构的强大技术。将酶与底物/产物的复合物可视化并捕捉中间状态,可将其与活性联系起来,从而促进对催化机理的理解。随后对酶活性位点内的小分子结合进行分析,可以深入了解抑制机制,从而支持利用结构引导方法设计新型抑制剂。首次测定的 X 射线晶体结构适用于小型、无处不在的酶,如碳酸酐酶(CA)。碳酸酐酶是锌金属酶家族的一种,可催化二氧化碳水合,产生 HCO3 和质子。人们已经对 CA 的结构和乒乓机制进行了广泛的研究,并对其有了深入的了解。尽管 CA 的功能在多种生理功能中发挥着重要作用,但 CA 也与青光眼、水肿、癫痫、肥胖和癌症等疾病有关,因此被公认为药物靶点。在这篇综述中,将简要讨论晶体学的历史及其对 CA 研究的影响。
Crystallography and Its Impact on Carbonic Anhydrase Research.
X-ray and neutron crystallography are powerful techniques utilized to study the structures of biomolecules. Visualization of enzymes in complex with substrate/product and the capture of intermediate states can be related to activity to facilitate understanding of the catalytic mechanism. Subsequent analysis of small molecule binding within the enzyme active site provides insight into mechanisms of inhibition, supporting the design of novel inhibitors using a structure-guided approach. The first X-ray crystal structures were determined for small, ubiquitous enzymes such as carbonic anhydrase (CA). CAs are a family of zinc metalloenzymes that catalyze the hydration of CO2, producing HCO3- and a proton. The CA structure and ping-pong mechanism have been extensively studied and are well understood. Though the function of CA plays an important role in a variety of physiological functions, CA has also been associated with diseases such as glaucoma, edema, epilepsy, obesity, and cancer and is therefore recognized as a drug target. In this review, a brief history of crystallography and its impact on CA research is discussed.
期刊介绍:
International Journal of Medicinal Chemistry is a peer-reviewed, Open Access journal that publishes original research articles as well as review articles in all areas of chemistry associated with drug discovery, design, and synthesis. International Journal of Medicinal Chemistry is a peer-reviewed, Open Access journal that publishes original research articles as well as review articles in all areas of chemistry associated with drug discovery, design, and synthesis.