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

Abstract 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 K D 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.

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Publication Details

Journal
Nature Communications
Published
2026-05-18
DOI
https://doi.org/10.1038/s41467-026-71345-8
Primary Topic
Chemical Synthesis and Analysis
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Suna Cheng, Brian Coventry, Asim K. Bera, Meerit Y. Said et al.
Nature Communications
Chemical Synthesis and Analysis
article

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

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

Abstract

Abstract 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 K D 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.

Nature Communications
University of Washington (US), Fred Hutch Cancer Center (US), PDL BioPharma (United States) (US)
National Science Foundation, Howard Hughes Medical Institute, U.S. Department of Energy, Bill and Melinda Gates Foundation, Juvenile Diabetes Research Foundation International, Open Philanthropy Project, National Institutes of Health, Defense Advanced Research Projects Agency, Office of Science, Advanced Research Projects Agency, Spark Therapeutics, National Institute of General Medical Sciences, Division of Chemistry, Argonne National Laboratory
Openalex Percentile: Top 8%
Chemical Synthesis and Analysis
DOIOpen Access PDFOpenAlex
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