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Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt.

de Vries RMJM, Meijer FA, Doveston RG, Leijten-van de Gevel IA, Brunsveld L
Proc Natl Acad Sci U S A 118 (2021)
Related entries: 6t4g, 6t4i, 6t4j, 6t4k, 6t4t, 6t4u, 6t4w, 6t4x, 6t4y, 6tlq, 6tlt

Cited: 17 times
EuropePMC logo PMID: 33536342

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.

Articles - 6t50 mentioned but not cited (1)

  1. Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt. de Vries RMJM, Meijer FA, Doveston RG, Leijten-van de Gevel IA, Brunsveld L. Proc Natl Acad Sci U S A 118 e2021287118 (2021)


Reviews citing this publication (3)

  1. AlphaFold, Artificial Intelligence (AI), and Allostery. Nussinov R, Zhang M, Liu Y, Jang H. J Phys Chem B 126 6372-6383 (2022)
  2. Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs. Nussinov R, Zhang M, Maloney R, Liu Y, Tsai CJ, Jang H. J Mol Biol 434 167569 (2022)
  3. Recent applications of computational methods to allosteric drug discovery. Govindaraj RG, Thangapandian S, Schauperl M, Denny RA, Diller DJ. Front Mol Biosci 9 1070328 (2022)

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  1. Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development. Manickam Y, Malhotra N, Mishra S, Babbar P, Dusane A, Laleu B, Bellini V, Hakimi MA, Bougdour A, Sharma A. PLoS Pathog 18 e1010363 (2022)
  2. Cooperativity as quantification and optimization paradigm for nuclear receptor modulators. de Vink PJ, Koops AA, D'Arrigo G, Cruciani G, Spyrakis F, Brunsveld L. Chem Sci 13 2744-2752 (2022)
  3. Orthosteric and Allosteric Dual Targeting of the Nuclear Receptor RORγt with a Bitopic Ligand. Meijer FA, Oerlemans GJM, Brunsveld L. ACS Chem Biol 16 510-519 (2021)
  4. Structure-Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor γt. Meijer FA, Saris AOWM, Doveston RG, Oerlemans GJM, de Vries RMJM, Somsen BA, Unger A, Klebl B, Ottmann C, Cossar PJ, Brunsveld L. J Med Chem 64 9238-9258 (2021)
  5. Covalent Occlusion of the RORγt Ligand Binding Pocket Allows Unambiguous Targeting of an Allosteric Site. Meijer FA, van den Oetelaar MCM, Doveston RG, Sampers ENR, Brunsveld L. ACS Med Chem Lett 12 631-639 (2021)
  6. Errors in structural biology are not the exception. Gao Y, Thorn V, Thorn A. Acta Crystallogr D Struct Biol 79 206-211 (2023)
  7. New Insight Into the Structure-Activity Relationship of Sweet-Tasting Proteins: Protein Sector and Its Role for Sweet Properties. Zhao X, Wang C, Zheng Y, Liu B. Front Nutr 8 691368 (2021)
  8. Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs. Li F, Song C, Zhang Y, Wu D. Acta Biochim Biophys Sin (Shanghai) 54 12-24 (2022)
  9. Camouflaged angiogenic BMP-2 functions exposed by pico-paracrine biohybrids. Jennissen HP. Front Bioeng Biotechnol 11 1226649 (2023)
  10. Ginseng-derived panaxadiol ameliorates STZ-induced type 1 diabetes through inhibiting RORγ/IL-17A axis. Tian SY, Chen SM, Feng YY, He JL, Li Y. Acta Pharmacol Sin 44 1217-1226 (2023)
  11. Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ. Pham B, Cheng Z, Lopez D, Lindsay RJ, Foutch D, Majors RT, Shen T. Front Mol Biosci 9 904445 (2022)
  12. Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation. Liu Y, Ma L, Li M, Tian Z, Yang M, Wu X, Wang X, Shang G, Xie M, Chen Y, Liu X, Jiang L, Wu W, Xu C, Xia L, Li G, Dai S, Chen Z. Nucleic Acids Res 51 1443-1457 (2023)
  13. Targeting the Alternative Vitamin E Metabolite Binding Site Enables Noncanonical PPARγ Modulation. Arifi S, Marschner JA, Pollinger J, Isigkeit L, Heitel P, Kaiser A, Obeser L, Höfner G, Proschak E, Knapp S, Chaikuad A, Heering J, Merk D. J Am Chem Soc 145 14802-14810 (2023)


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