气候变化领域集成服务门户(CCPortal): De novo design of tunable, pH-driven conformational changes

CCPortal

DOI	10.1126/science.aav7897
	De novo design of tunable, pH-driven conformational changes
	Boyken S.E.; Benhaim M.A.; Busch F.; Jia M.; Bick M.J.; Choi H.; Klima J.C.; Chen Z.; Walkey C.; Mileant A.; Sahasrabuddhe A.; Wei K.Y.; Hodge E.A.; Byron S.; Quijano-Rubio A.; Sankaran B.; King N.P.; Lippincott-Schwartz J.; Wysocki V.H.; Lee K.K.; Baker D.
发表日期	2019
ISSN	0036-8075
起始页码	658
结束页码	664
卷号	364 期号:6442
英文摘要	The ability of naturally occurring proteins to change conformation in response to environmental changes is critical to biological function. Although there have been advances in the de novo design of stable proteins with a single, deep free-energy minimum, the design of conformational switches remains challenging. We present a general strategy to design pH-responsive protein conformational changes by precisely preorganizing histidine residues in buried hydrogen-bond networks. We design homotrimers and heterodimers that are stable above pH 6.5 but undergo cooperative, large-scale conformational changes when the pH is lowered and electrostatic and steric repulsion builds up as the network histidine residues become protonated. The transition pH and cooperativity can be controlled through the number of histidine-containing networks and the strength of the surrounding hydrophobic interactions. Upon disassembly, the designed proteins disrupt lipid membranes both in vitro and after being endocytosed in mammalian cells. Our results demonstrate that environmentally triggered conformational changes can now be programmed by de novo protein design. © 2019 American Association for the Advancement of Science. All rights reserved.
英文关键词	heterodimer; histidine; homotrimer; polymer; unclassified drug; amino acid; cell component; chemical bonding; environmental change; hydrophobicity; lipid; mammal; membrane; pH; protein; amino acid sequence; Article; conformational transition; endocytosis; environmental factor; hydrogen bond; hydrophobicity; in vitro study; lipid membrane; molecular interaction; pH; priority journal; protein assembly; protein conformation; protein stability; protonation; static electricity; pH; procedures; protein engineering; protein multimerization; Mammalia; Hydrogen-Ion Concentration; Protein Conformation; Protein Engineering; Protein Multimerization; Protein Stability
语种	英语
来源期刊	Science
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/243119
作者单位	Department of Biochemistry, University of Washington, Seattle, WA 98195, United States; Institute for Protein Design, University of Washington, Seattle, WA 98195, United States; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States; Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH 43210, United States; Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147, United States; Graduate Program in Biological Physics, Structure, and Design, University of Washington, Seattle, WA, United States; Department of Bioengineering, University of California, Berkeley, CA 94720, United States; Department of Bioengineering, University of Washington, Seattle, WA 98195, United States; Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, United States; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, United States
推荐引用方式 GB/T 7714	Boyken S.E.,Benhaim M.A.,Busch F.,et al. De novo design of tunable, pH-driven conformational changes[J],2019,364(6442).
APA	Boyken S.E..,Benhaim M.A..,Busch F..,Jia M..,Bick M.J..,...&Baker D..(2019).De novo design of tunable, pH-driven conformational changes.Science,364(6442).
MLA	Boyken S.E.,et al."De novo design of tunable, pH-driven conformational changes".Science 364.6442(2019).