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<p>Investigating and manipulating cellular events requires precise control of protein function. To enable control over cellular processes, we set out to design a chemically induced dimerization (CID) system consisting of a de novo-designed ligand and protein pair. Here, we describe the design of a C2 symmetric membrane-permeable macrocyclic peptide and a&#xa0;cognate protein homodimer which binds the macrocycle through a&#xa0;large interface with both chains. The designed homodimer binds the macrocycle with a <i>K</i><sub>D</sub> of 36 nM, and the x-ray crystal structure of the protein homodimer-macrocycle complex is very close to the computational design model, with the C2 axis of the macrocycle aligned with the homodimer C2 axis. Transcriptional and split luciferase assays in mammalian cells demonstrate conditional control over both a reporter gene expression and luciferase reconstitution.</p>

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De novo design of a macrocycle-induced dimerization system for cellular control

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月18日

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  • Stephanie Hanna,
  • Patrick J. Salveson,
  • Basile Wicky,
  • Madison A. Kennedy,
  • Derrick R. Hicks,
  • Carolina Moller,
  • Suna Cheng,
  • Xinting Li,
  • Mohamad Abedi,
  • Brian Coventry,
  • Meerit Y. Said,
  • Asim K. Bera,
  • Alex Kang,
  • Barry L. Stoddard,
  • David Baker

摘要

Investigating and manipulating cellular events requires precise control of protein function. To enable control over cellular processes, we set out to design a chemically induced dimerization (CID) system consisting of a de novo-designed ligand and protein pair. Here, we describe the design of a C2 symmetric membrane-permeable macrocyclic peptide and a cognate protein homodimer which binds the macrocycle through a large interface with both chains. The designed homodimer binds the macrocycle with a KD of 36 nM, and the x-ray crystal structure of the protein homodimer-macrocycle complex is very close to the computational design model, with the C2 axis of the macrocycle aligned with the homodimer C2 axis. Transcriptional and split luciferase assays in mammalian cells demonstrate conditional control over both a reporter gene expression and luciferase reconstitution.