气候变化领域集成服务门户(CCPortal): Mechanistic basis of propofol-induced disruption of kinesin processivity

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DOI	10.1073/pnas.2023659118
	Mechanistic basis of propofol-induced disruption of kinesin processivity
	Dutta M.; Gilbert S.P.; Onuchic J.N.; Jana B.
发表日期	2021
ISSN	00278424
卷号	118 期号:5
英文摘要	Propofol is a widely used general anesthetic to induce and maintain anesthesia, and its effects are thought to occur through impact on the ligand-gated channels including the GABAA receptor. Propofol also interacts with a large number of proteins including molecular motors and inhibits kinesin processivity, resulting in significant decrease in the run length for conventional kinesin-1 and kinesin-2. However, the molecular mechanism by which propofol achieves this outcome is not known. The structural transition in the kinesin neck-linker region is crucial for its processivity. In this study, we analyzed the effect of propofol and its fluorine derivative (fropofol) on the transition in the neck-linker region of kinesin. Propofol binds at two crucial surfaces in the leading head: one at the microtubule-binding interface and the other in the neck-linker region. We observed in both the cases the order–disorder transition of the neck-linker was disrupted and kinesin lost its signal for forward movement. In contrast, there was not an effect on the neck-linker transition with propofol binding at the trailing head. Free-energy calculations show that propofol at the microtubule-binding surface significantly reduces the microtubule-binding affinity of the kinesin head. While propofol makes pi–pi stacking and H-bond interactions with the propofol binding cavity, fropofol is unable to make a suitable interaction at this binding surface. Therefore, the binding affinity of fropofol is much lower compared to propofol. Hence, this study provides a mechanism by which propofol disrupts kinesin processivity and identifies transitions in the ATPase stepping cycle likely affected. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Anesthetic mechanism; Fropofol; Kinesin; Neuron; Propofol
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180833
作者单位	School of Chemical Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, 700032, India; Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, United States; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, United States; Department of Chemistry, Rice University, Houston, TX 77030, United States; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, United States; Department of Physics and Astronomy, Rice University, Houston, TX 77030, United States; Department of Biosciences, Rice University, Houston, TX 77030, United States
推荐引用方式 GB/T 7714	Dutta M.,Gilbert S.P.,Onuchic J.N.,et al. Mechanistic basis of propofol-induced disruption of kinesin processivity[J],2021,118(5).
APA	Dutta M.,Gilbert S.P.,Onuchic J.N.,&Jana B..(2021).Mechanistic basis of propofol-induced disruption of kinesin processivity.Proceedings of the National Academy of Sciences of the United States of America,118(5).
MLA	Dutta M.,et al."Mechanistic basis of propofol-induced disruption of kinesin processivity".Proceedings of the National Academy of Sciences of the United States of America 118.5(2021).