Year: 2026
Type: article
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.
Source: Nature Communications
Institutions: University of Washington, Fred Hutch Cancer Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: 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, National Institute of Allergy and Infectious Diseases, Division of Chemistry, Argonne National Laboratory
Awards: G102163711, G1260661382, G1313983767, G1664757510, G2287611682, G2509822656, G2515541506, G262962599, G3075337988, G409777406, Graduate Research Fellowship Program (GRFP), G4915607158, G498139845, G513797252, G5607048534, Generation, functionalization, and distribution of de novo designed protein nanomaterials, G6848031779, G6918803902, G754259764, University of Washington Foundation - to support structure based immunogen design for next-generation vaccines, G7878662916, Acquisition of a Rigaku XtaLAB Synergy-R macromolecular diffraction instrumentation at Fred Hutchinson Cancer Research Center, G8677427408, G9000239240, De Novo Design of Minibinder Antagonists for COVID-19 and Future Pandemics, G969889393
OpenAlex ID: W7161571156