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1. The glucocorticoid receptor potentiates aldosterone-induced transcription by the mineralocorticoid receptor

   https://doi.org/10.1073/pnas.2413737121  

   Johnson, Thomas_A; Fettweis, Gregory; Wagh, Kaustubh; Ceacero-Heras, Diego; Krishnamurthy, Manan; Sánchez_de_Medina, Fermín; Martínez-Augustin, Olga; Upadhyaya, Arpita; Hager, Gordon_L; Alvarez_de_la_Rosa, Diego (November 2024, Proceedings of the National Academy of Sciences)

   The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indications that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR coexpression on MR genome-wide transcriptional responses and chromatin binding upon activation by aldosterone and glucocorticoids, both physiological ligands of this receptor. Transcriptional responses of MR in the absence of GR result in fewer regulated genes. In contrast, coexpression of GR potentiates MR-mediated transcription, particularly in response to aldosterone, both in cell lines and in the more physiologically relevant model of mouse colon organoids. MR chromatin binding is altered by GR coexpression in a locus- and ligand-specific way. Single-molecule tracking of MR suggests that the presence of GR contributes to productive binding of MR/aldosterone complexes to chromatin. Together, our data indicate that coexpression of GR potentiates aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids. 

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2. Naturally Occurring Genetic Variants in the Oxytocin Receptor Alter Receptor Signaling Profiles

   https://doi.org/10.1021/acsptsci.1c00095  

   Malik, M; Ward, MD.; Fang, Y; Porter, JR.; Zimmerman, MI; Koelblen, T; Roh, M; Frolova, AI; Burris, TP; Bowman, GR; et al (September 2021, ACS pharmacology translational science)
3. The evolution of synthetic receptor systems

   https://doi.org/10.1038/s41589-021-00926-z  

   Manhas, Janvie; Edelstein, Hailey I; Leonard, Joshua N; Morsut, Leonardo (March 2022, Nature Chemical Biology)
4. The discriminatory power of the T cell receptor

   https://doi.org/10.7554/eLife.67092  

   Pettmann, Johannes; Huhn, Anna; Abu Shah, Enas; Kutuzov, Mikhail A; Wilson, Daniel B; Dustin, Michael L; Davis, Simon J; van der Merwe, P Anton; Dushek, Omer (May 2021, eLife)

   T cells use their T cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self peptides presented on major histocompatibility complex (pMHC) antigens. Although the discriminatory power of the TCR is widely believed to be near-perfect, technical difficulties have hampered efforts to precisely quantify it. Here, we describe a method for measuring very low TCR/pMHC affinities and use it to measure the discriminatory power of the TCR and the factors affecting it. We find that TCR discrimination, although enhanced compared with conventional cell-surface receptors, is imperfect: primary human T cells can respond to pMHC with affinities as low as K D ∼ 1 mM. The kinetic proofreading mechanism fit our data, providing the first estimates of both the time delay (2.8 s) and number of biochemical steps (2.67) that are consistent with the extraordinary sensitivity of antigen recognition. Our findings explain why self pMHC frequently induce autoimmune diseases and anti-tumour responses, and suggest ways to modify TCR discrimination. 

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5. Exploring the Activation Process of the Glycine Receptor

   https://doi.org/10.1021/jacs.4c08489  

   Yan, Junfang; Chen, Luonan; Warshel, Arieh; Bai, Chen (September 2024, Journal of the American Chemical Society)

   Glycine receptors (GlyR) conduct inhibitory glycinergic neurotransmission in the spinal cord and the brainstem. They play an important role in muscle tone, motor coordination, respiration, and pain perception. However, the mechanism underlying GlyR activation remains unclear. There are five potential glycine binding sites in α1 GlyR, and different binding patterns may cause distinct activation or desensitization behaviors. In this study, we investigated the coupling of protein conformational changes and glycine binding events to elucidate the influence of binding patterns on the activation and desensitization processes of α1 GlyRs. Subsequently, we explored the energetic distinctions between the apical and lateral pathways during α1 GlyR conduction to identify the pivotal factors in the ion conduction pathway preference. Moreover, we predicted the mutational effects of the key residues and verified our predictions using electrophysiological experiments. For the mutants that can be activated by glycine, the predictions of the mutational directions were all correct. The strength of the mutational effects was assessed using Pearson’s correlation coefficient, yielding a value of −0.77 between the calculated highest energy barriers and experimental maximum current amplitudes. These findings contribute to our understanding of GlyR activation, identify the key residues of GlyRs, and provide guidance for mechanistic studies on other pLGICs. 

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