ArticleProceedings of the National Academy of Sciences of the United States of America2021
Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 31 citations in OpenAlex.
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- Targeting the Alternative Vitamin E Metabolite Binding Site Enables Noncanonical PPARγ Modulation.Journal of the American Chemical Society · 2023Article
- Ginseng-derived panaxadiol ameliorates STZ-induced type 1 diabetes through inhibiting RORγ/IL-17A axis.Acta pharmacologica Sinica · 2023Article
- Errors in structural biology are not the exception.Acta crystallographica. Section D, Structural biology · 2023Article
- Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation.Nucleic acids research · 2023Article
- Camouflaged angiogenic BMP-2 functions exposed by pico-paracrine biohybrids.Frontiers in bioengineering and biotechnology · 2023Article
- Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.Journal of molecular biology · 2022Review
- AlphaFold, Artificial Intelligence (AI), and Allostery.The journal of physical chemistry. B · 2022Review
- Cooperativity as quantification and optimization paradigm for nuclear receptor modulators.Chemical science · 2022Article
- Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development.PLoS pathogens · 2022Article
- Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs.Acta biochimica et biophysica Sinica · 2022Article
- Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ.Frontiers in molecular biosciences · 2022Article
- Recent applications of computational methods to allosteric drug discovery.Frontiers in molecular biosciences · 2022Review
- Structure-Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor γt.Journal of medicinal chemistry · 2021Article
- Covalent Occlusion of the RORγt Ligand Binding Pocket Allows Unambiguous Targeting of an Allosteric Site.ACS medicinal chemistry letters · 2021Article
- Orthosteric and Allosteric Dual Targeting of the Nuclear Receptor RORγt with a Bitopic Ligand.ACS chemical biology · 2021Article
- New Insight Into the Structure-Activity Relationship of Sweet-Tasting Proteins: Protein Sector and Its Role for Sweet Properties.Frontiers in nutrition · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.