Design of facilitated dissociation enables timing of cytokine signalling

article Design of facilitated dissociation enables timing of cytokine signalling published yes Adam J. Broerman author Christoph Pollmann author Yang Zhao author Mauriz A. Lichtenstein author Mark D. Jackson author Maxx H. Tessmer author Won Hee Ryu author Masato Ogishi author Mohamad H. Abedi author Danny D. Sahtoe author Aza Allen author Alex Kang author Joshmyn De La Cruz author Evans Brackenbrough author Banumathi Sankaran author Asim K. Bera author Daniel M. Zuckerman author Stefan Stoll author K. Christopher Garcia author Florian M Praetorius author dfec9381-4341-11ee-8fd8-faa02bba7d620000-0002-0806-8101 Jacob Piehler author David Baker author FlPr department Protein design has focused on the design of ground states, ensuring that they are sufficiently low energy to be highly populated1. Designing the kinetics and dynamics of a system requires, in addition, the design of excited states that are traversed in transitions from one low-lying state to another2,3. This is a challenging task because such states must be sufficiently strained to be poorly populated, but not so strained that they are not populated at all, and because protein design methods have focused on generating near-ideal structures4,5,6,7. Here we describe a general approach for designing systems that use an induced-fit power stroke8 to generate a structurally frustrated9 and strained excited state, allosterically driving protein complex dissociation. X-ray crystallography, double electron–electron resonance spectroscopy and kinetic binding measurements show that incorporating excited states enables the design of effector-induced increases in dissociation rates as high as 5,700-fold. We highlight the power of this approach by designing rapid biosensors, kinetically controlled circuits and cytokine mimics that can be dissociated from their receptors within seconds, enabling dissection of the temporal dynamics of interleukin-2 signalling. https://research-explorer.ista.ac.at/download/20430/20951/2025_Nature_Broerman.pdf application/pdfno https://creativecommons.org/licenses/by/4.0/ Springer Nature2025 eng Nature 0028-0836 1476-4687 40993395 00157775560000110.1038/s41586-025-09549-z 647528-535 A. J. Broerman et al., “Design of facilitated dissociation enables timing of cytokine signalling,” Nature, vol. 647. Springer Nature, pp. 528–535, 2025. Broerman, A. J., Pollmann, C., Zhao, Y., Lichtenstein, M. A., Jackson, M. D., Tessmer, M. H., … Baker, D. (2025). Design of facilitated dissociation enables timing of cytokine signalling. Nature. Springer Nature. <a href="https://doi.org/10.1038/s41586-025-09549-z">https://doi.org/10.1038/s41586-025-09549-z</a> Broerman, Adam J., Christoph Pollmann, Yang Zhao, Mauriz A. Lichtenstein, Mark D. Jackson, Maxx H. Tessmer, Won Hee Ryu, et al. “Design of Facilitated Dissociation Enables Timing of Cytokine Signalling.” Nature. Springer Nature, 2025. <a href="https://doi.org/10.1038/s41586-025-09549-z">https://doi.org/10.1038/s41586-025-09549-z</a>. Broerman AJ, Pollmann C, Zhao Y, Lichtenstein MA, Jackson MD, Tessmer MH, Ryu WH, Ogishi M, Abedi MH, Sahtoe DD, Allen A, Kang A, De La Cruz J, Brackenbrough E, Sankaran B, Bera AK, Zuckerman DM, Stoll S, Garcia KC, Praetorius FM, Piehler J, Baker D. 2025. Design of facilitated dissociation enables timing of cytokine signalling. Nature. 647, 528–535. A.J. Broerman, C. Pollmann, Y. Zhao, M.A. Lichtenstein, M.D. Jackson, M.H. Tessmer, W.H. Ryu, M. Ogishi, M.H. Abedi, D.D. Sahtoe, A. Allen, A. Kang, J. De La Cruz, E. Brackenbrough, B. Sankaran, A.K. Bera, D.M. Zuckerman, S. Stoll, K.C. Garcia, F.M. Praetorius, J. Piehler, D. Baker, Nature 647 (2025) 528–535. Broerman AJ, Pollmann C, Zhao Y, et al. Design of facilitated dissociation enables timing of cytokine signalling. Nature. 2025;647:528-535. doi:<a href="https://doi.org/10.1038/s41586-025-09549-z">10.1038/s41586-025-09549-z</a> Broerman, Adam J., et al. “Design of Facilitated Dissociation Enables Timing of Cytokine Signalling.” Nature, vol. 647, Springer Nature, 2025, pp. 528–35, doi:<a href="https://doi.org/10.1038/s41586-025-09549-z">10.1038/s41586-025-09549-z</a>. 204302025-10-05T22:01:36Z2026-01-05T13:18:17Z