---
_id: '17463'
abstract:
- lang: eng
  text: Allosteric modulation of protein function, wherein the binding of an effector
    to a protein triggers conformational changes at distant functional sites, plays
    a central part in the control of metabolism and cell signalling1,2,3. There has
    been considerable interest in designing allosteric systems, both to gain insight
    into the mechanisms underlying such ‘action at a distance’ modulation and to create
    synthetic proteins whose functions can be regulated by effectors4,5,6,7. However,
    emulating the subtle conformational changes distributed across many residues,
    characteristic of natural allosteric proteins, is a significant challenge8,9.
    Here, inspired by the classic Monod–Wyman–Changeux model of cooperativity10, we
    investigate the de novo design of allostery through rigid-body coupling of peptide-switchable
    hinge modules11 to protein interfaces12 that direct the formation of alternative
    oligomeric states. We find that this approach can be used to generate a wide variety
    of allosterically switchable systems, including cyclic rings that incorporate
    or eject subunits in response to peptide binding and dihedral cages that undergo
    effector-induced disassembly. Size-exclusion chromatography, mass photometry13
    and electron microscopy reveal that these designed allosteric protein assemblies
    closely resemble the design models in both the presence and absence of peptide
    effectors and can have ligand-binding cooperativity comparable to classic natural
    systems such as haemoglobin14. Our results indicate that allostery can arise from
    global coupling of the energetics of protein substructures without optimized side-chain–side-chain
    allosteric communication pathways and provide a roadmap for generating allosterically
    triggerable delivery systems, protein nanomachines and cellular feedback control
    circuitry.
acknowledgement: We thank D. D. Sahtoe, R. D. Kiber, Y. Hsia, N. Bethel and A. Favor
  for helpful discussions and K. VanWormer and L. Goldschmidt for technical support.
  We also thank X. Li and M. Lamb for mass spectrometry support. This work was supported
  by the Washington Research Foundation Postdoctoral Fellowship (grant no. GR027504,
  A. Pillai), a National Science Foundation Graduate Research Fellowship (grant no.
  DGE-2140004, A.I.), a Human Frontier Science Program Long Term Fellowship (grant
  no. LT000880/2019, F.P.), the Audacious Project at the Institute for Protein Design
  (A.B., A. Pillai, A. Philomin, A.I. and D.B.), a National Energy Research Scientific
  Computing Centre award (grant no. BER-ERCAP0022018), the Howard Hughes Medical Institute
  (D.B.), the Open Philanthropy Project Improving Protein Design Fund (P.J.Y.L., C.D.
  and D.B.) a gift from Microsoft (D.B.) and a grant from DARPA supporting the Harnessing
  Enzymatic Activity for Lifesaving Remedies programme (grant no. HR001120S0052, contract
  no. HR0011-21-2-0012, D.B.).
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Arvind
  full_name: Pillai, Arvind
  last_name: Pillai
- first_name: Abbas
  full_name: Idris, Abbas
  last_name: Idris
- first_name: Annika
  full_name: Philomin, Annika
  last_name: Philomin
- first_name: Connor
  full_name: Weidle, Connor
  last_name: Weidle
- first_name: Rebecca
  full_name: Skotheim, Rebecca
  last_name: Skotheim
- first_name: Philip J.Y.
  full_name: Leung, Philip J.Y.
  last_name: Leung
- first_name: Adam
  full_name: Broerman, Adam
  last_name: Broerman
- first_name: Cullen
  full_name: Demakis, Cullen
  last_name: Demakis
- first_name: Andrew J.
  full_name: Borst, Andrew J.
  last_name: Borst
- first_name: Florian M
  full_name: Praetorius, Florian M
  id: dfec9381-4341-11ee-8fd8-faa02bba7d62
  last_name: Praetorius
- first_name: David
  full_name: Baker, David
  last_name: Baker
citation:
  ama: Pillai A, Idris A, Philomin A, et al. De novo design of allosterically switchable
    protein assemblies. <i>Nature</i>. 2024;632:911–920. doi:<a href="https://doi.org/10.1038/s41586-024-07813-2">10.1038/s41586-024-07813-2</a>
  apa: Pillai, A., Idris, A., Philomin, A., Weidle, C., Skotheim, R., Leung, P. J.
    Y., … Baker, D. (2024). De novo design of allosterically switchable protein assemblies.
    <i>Nature</i>. Springer Nature. <a href="https://doi.org/10.1038/s41586-024-07813-2">https://doi.org/10.1038/s41586-024-07813-2</a>
  chicago: Pillai, Arvind, Abbas Idris, Annika Philomin, Connor Weidle, Rebecca Skotheim,
    Philip J.Y. Leung, Adam Broerman, et al. “De Novo Design of Allosterically Switchable
    Protein Assemblies.” <i>Nature</i>. Springer Nature, 2024. <a href="https://doi.org/10.1038/s41586-024-07813-2">https://doi.org/10.1038/s41586-024-07813-2</a>.
  ieee: A. Pillai <i>et al.</i>, “De novo design of allosterically switchable protein
    assemblies,” <i>Nature</i>, vol. 632. Springer Nature, pp. 911–920, 2024.
  ista: Pillai A, Idris A, Philomin A, Weidle C, Skotheim R, Leung PJY, Broerman A,
    Demakis C, Borst AJ, Praetorius FM, Baker D. 2024. De novo design of allosterically
    switchable protein assemblies. Nature. 632, 911–920.
  mla: Pillai, Arvind, et al. “De Novo Design of Allosterically Switchable Protein
    Assemblies.” <i>Nature</i>, vol. 632, Springer Nature, 2024, pp. 911–920, doi:<a
    href="https://doi.org/10.1038/s41586-024-07813-2">10.1038/s41586-024-07813-2</a>.
  short: A. Pillai, A. Idris, A. Philomin, C. Weidle, R. Skotheim, P.J.Y. Leung, A.
    Broerman, C. Demakis, A.J. Borst, F.M. Praetorius, D. Baker, Nature 632 (2024)
    911–920.
corr_author: '1'
date_created: 2024-08-25T22:01:08Z
date_published: 2024-08-22T00:00:00Z
date_updated: 2025-09-08T09:00:16Z
day: '22'
ddc:
- '570'
department:
- _id: FlPr
doi: 10.1038/s41586-024-07813-2
external_id:
  isi:
  - '001300534300019'
  pmid:
  - '39143214'
file:
- access_level: open_access
  checksum: 39127601621a360ec0edc538627eb211
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  creator: dernst
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  date_updated: 2024-09-09T12:01:14Z
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has_accepted_license: '1'
intvolume: '       632'
isi: 1
language:
- iso: eng
license: https://creativecommons.org/licenses/by-nc-nd/4.0/
month: '08'
oa: 1
oa_version: Published Version
page: '911–920 '
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: De novo design of allosterically switchable protein assemblies
tmp:
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  name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
    (CC BY-NC-ND 4.0)
  short: CC BY-NC-ND (4.0)
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user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345
volume: 632
year: '2024'
...