气候变化领域集成服务门户(CCPortal): Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt

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DOI	10.1073/pnas.2021287118
	Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt
	de Vries R.M.J.M.; Meijer F.A.; Doveston R.G.; Leijten-Van de Gevel I.A.; Brunsveld L.
发表日期	2021
ISSN	00278424
卷号	118 期号:6
英文摘要	Cooperative ligand binding is an important phenomenon in biological systems where ligand binding influences the binding of another ligand at an alternative site of the protein via an intramolecular network of interactions. The underlying mechanisms behind cooperative binding remain poorly understood, primarily due to the lack of structural data of these ternary complexes. Using time-resolved fluorescence resonance energy transfer (TR-FRET) studies, we show that cooperative ligand binding occurs for RORγt, a nuclear receptor associated with the pathogenesis of autoimmune diseases. To provide the crucial structural insights, we solved 12 crystal structures of RORγt simultaneously bound to various orthosteric and allosteric ligands. The presence of the orthosteric ligand induces a clamping motion of the allosteric pocket via helices 4 to 5. Additional molecular dynamics simulations revealed the unusual mechanism behind this clamping motion, with Ala355 shifting between helix 4 and 5. The orthosteric RORγt agonists regulate the conformation of Ala355, thereby stabilizing the conformation of the allosteric pocket and cooperatively enhancing the affinity of the allosteric inverse agonists. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Allosteric modulators; Drug discovery; Nuclear receptors; RORγt; Structure elucidation
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/180737
作者单位	Laboratory of Chemical Biology, Department of Biomedical Engineering, Technische Universiteit Eindhoven, Eindhoven, 5612 AZ, Netherlands; Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Eindhoven, 5612 AZ, Netherlands; Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, LE1 7RH, United Kingdom; School of Chemistry, University of Leicester, Leicester, LE1 7RH, United Kingdom
推荐引用方式 GB/T 7714	de Vries R.M.J.M.,Meijer F.A.,Doveston R.G.,et al. Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt[J],2021,118(6).
APA	de Vries R.M.J.M.,Meijer F.A.,Doveston R.G.,Leijten-Van de Gevel I.A.,&Brunsveld L..(2021).Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt.Proceedings of the National Academy of Sciences of the United States of America,118(6).
MLA	de Vries R.M.J.M.,et al."Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt".Proceedings of the National Academy of Sciences of the United States of America 118.6(2021).