---
OA_place: publisher
OA_type: hybrid
PlanS_conform: '1'
_id: '20430'
abstract:
- lang: eng
  text: 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.
acknowledgement: We thank P. J. Y. Leung, K. L. Shelley, A. Pillai, C. Demakis, M.
  Exposit, K. Thompson, C. Savvides, R. J. Ragotte, G. Ahn and M. Glögl for discussions
  and technical support; K. VanWormer and L. Goldschmidt for technical support; S.
  R. Gerben and A. Murray for protein production support; and X. Li, M. Lamb, Z. Taylor
  and V. Adebomi for LC–MS support. This work was supported by the Audacious Project
  at the Institute for Protein Design (A.J.B., A.K., J.D.L.C., E.B. and A.K.B.); by
  a gift from Microsoft (A.J.B.); by the Nordstrom Barrier Institute for Protein Design
  Directors Fund (M.H.A. and F.P.); by Bill and Melinda Gates Foundation OPP1156262
  (A.K. and J.D.L.C.); by the Open Philanthropy Project Improving Protein Design Fund
  (E.B. and A.K.B.); by the National Institutes of Health (NIH) National Institute
  of Allergy and Infectious Disease grant R0AI160052 (A.K.B.); by CRI Irvington Postdoctoral
  Fellowship 315511 (Y.Z.); by National Cancer Institute K00 award 4K00CA274708 (M.O.);
  by National Science Foundation grant MCB 2119837 and NIH grant GM115805 (W.H.R.
  and D.M.Z.); by NIH grant GM151956 (S.S.); by NIH AI-51321 (K.C.G.); by the DFG
  grants PI 405/15 and SFB 1557 (C.P. and J.P.); and by the Howard Hughes Medical
  Institute (A.K.B., K.C.G. and D.B.). The EPR spectrometer used for the DEER experiments
  was in part supported by NIH grant S10OD021557. This research used resources (FMX/AMX)
  of the National Synchrotron Light Source II, a US Department of Energy (DoE) Office
  of Science User Facility operated for the DOE Office of Science by Brookhaven National
  Laboratory under contract DE-SC0012704. The Center for BioMolecular Structure (CBMS)
  is supported mainly by the NIH National Institute of General Medical Sciences (NIGMS)
  through a Center Core P30 Grant (P30GM133893), and by the DoE Office of Biological
  and Environmental Research (KP1607011). This work is based on research performed
  at the Northeastern Collaborative Access Team beamlines, which are funded by the
  NIGMS (P30 GM124165). The research used resources of the Advanced Photon Source,
  a US DoE Office of Science User Facility operated for the DoE Office of Science
  by Argonne National Laboratory under contract DE-AC02-06CH11357. The Berkeley Center
  for Structural Biology is supported by the NIH, NIGMS and the Howard Hughes Medical
  Institute. The Advanced Light Source is supported by the Director, Office of Science,
  Office of Basic Energy Sciences and US DoE (DE-AC02-05CH11231).
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Adam J.
  full_name: Broerman, Adam J.
  last_name: Broerman
- first_name: Christoph
  full_name: Pollmann, Christoph
  last_name: Pollmann
- first_name: Yang
  full_name: Zhao, Yang
  last_name: Zhao
- first_name: Mauriz A.
  full_name: Lichtenstein, Mauriz A.
  last_name: Lichtenstein
- first_name: Mark D.
  full_name: Jackson, Mark D.
  last_name: Jackson
- first_name: Maxx H.
  full_name: Tessmer, Maxx H.
  last_name: Tessmer
- first_name: Won Hee
  full_name: Ryu, Won Hee
  last_name: Ryu
- first_name: Masato
  full_name: Ogishi, Masato
  last_name: Ogishi
- first_name: Mohamad H.
  full_name: Abedi, Mohamad H.
  last_name: Abedi
- first_name: Danny D.
  full_name: Sahtoe, Danny D.
  last_name: Sahtoe
- first_name: Aza
  full_name: Allen, Aza
  last_name: Allen
- first_name: Alex
  full_name: Kang, Alex
  last_name: Kang
- first_name: Joshmyn
  full_name: De La Cruz, Joshmyn
  last_name: De La Cruz
- first_name: Evans
  full_name: Brackenbrough, Evans
  last_name: Brackenbrough
- first_name: Banumathi
  full_name: Sankaran, Banumathi
  last_name: Sankaran
- first_name: Asim K.
  full_name: Bera, Asim K.
  last_name: Bera
- first_name: Daniel M.
  full_name: Zuckerman, Daniel M.
  last_name: Zuckerman
- first_name: Stefan
  full_name: Stoll, Stefan
  last_name: Stoll
- first_name: K. Christopher
  full_name: Garcia, K. Christopher
  last_name: Garcia
- first_name: Florian M
  full_name: Praetorius, Florian M
  id: dfec9381-4341-11ee-8fd8-faa02bba7d62
  last_name: Praetorius
  orcid: 0000-0002-0806-8101
- first_name: Jacob
  full_name: Piehler, Jacob
  last_name: Piehler
- first_name: David
  full_name: Baker, David
  last_name: Baker
citation:
  ama: Broerman AJ, Pollmann C, Zhao Y, et al. Design of facilitated dissociation
    enables timing of cytokine signalling. <i>Nature</i>. 2025;647:528-535. doi:<a
    href="https://doi.org/10.1038/s41586-025-09549-z">10.1038/s41586-025-09549-z</a>
  apa: 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. <i>Nature</i>. Springer Nature. <a href="https://doi.org/10.1038/s41586-025-09549-z">https://doi.org/10.1038/s41586-025-09549-z</a>
  chicago: 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.” <i>Nature</i>. Springer Nature, 2025.
    <a href="https://doi.org/10.1038/s41586-025-09549-z">https://doi.org/10.1038/s41586-025-09549-z</a>.
  ieee: A. J. Broerman <i>et al.</i>, “Design of facilitated dissociation enables
    timing of cytokine signalling,” <i>Nature</i>, vol. 647. Springer Nature, pp.
    528–535, 2025.
  ista: 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.
  mla: Broerman, Adam J., et al. “Design of Facilitated Dissociation Enables Timing
    of Cytokine Signalling.” <i>Nature</i>, 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>.
  short: 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.
corr_author: '1'
date_created: 2025-10-05T22:01:36Z
date_published: 2025-11-13T00:00:00Z
date_updated: 2026-01-05T13:18:17Z
day: '13'
ddc:
- '570'
department:
- _id: FlPr
doi: 10.1038/s41586-025-09549-z
external_id:
  isi:
  - '001577755600001'
  pmid:
  - '40993395'
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fulldoi: https://doi.org/10.1038/s41586-025-09549-z
has_accepted_license: '1'
intvolume: '       647'
isi: 1
language:
- iso: eng
month: '11'
oa: 1
oa_version: Published Version
page: 528-535
pmid: 1
publication: Nature
publication_identifier:
  eissn:
  - 1476-4687
  issn:
  - 0028-0836
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Design of facilitated dissociation enables timing of cytokine signalling
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 647
year: '2025'
...