9DD3

Crystal Structure of Designed allosteric facilitated dissociation switch AS5 in complex state HE

9DD3 の概要

• エントリーDOI: 10.2210/pdb9dd3/pdb
• 分子名称: Designed allosteric facilitated dissociation switch AS5 H, Designed allosteric facilitated dissociation switch AS5 E (3 entities in total)
• 機能のキーワード: de novo protein, design model, effector, kinetics and dynamics, protein-protein interactions
• 由来する生物種: synthetic construct; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 31570.51

構造登録者

Bera, A.K.,Broerman, A.,Baker, D. (登録日: 2024-08-27, 公開日: 2025-08-20, 最終更新日: 2025-11-19)

主引用文献

Broerman, A.J.,Pollmann, C.,Zhao, Y.,Lichtenstein, M.A.,Jackson, M.D.,Tessmer, M.H.,Ryu, W.H.,Ogishi, M.,Abedi, M.H.,Sahtoe, D.D.,Allen, A.,Kang, A.,De La Cruz, J.,Brackenbrough, E.,Sankaran, B.,Bera, A.K.,Zuckerman, D.M.,Stoll, S.,Garcia, K.C.,Praetorius, F.,Piehler, J.,Baker, D.
Design of facilitated dissociation enables timing of cytokine signalling.
Nature, 647:528-535, 2025

PubMed Abstract: Protein design has focused on the design of ground states, ensuring that they are sufficiently low energy to be highly populated. 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 another. 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 structures. Here we describe a general approach for designing systems that use an induced-fit power stroke to generate a structurally frustrated 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.

PubMed: 40993395
DOI: 10.1038/s41586-025-09549-z

実験手法

X-RAY DIFFRACTION (1.64 Å)