8TM9

Computationally designed tunable C2 symmetric tandem repeat homodimer, D_3_633_8x bound to peptide

Summary for 8TM9

• Entry DOI: 10.2210/pdb8tm9/pdb
• Descriptor: D_3_633_8x peptide bound, MC1, N-PROPANOL, ... (5 entities in total)
• Functional Keywords: homodimer, de novo, designed, ctrp, computational, c2 symmetric, circular tandem repeat protein, cyclic peptide, de novo protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 3
• Total formula weight: 55551.39

Authors

Kennedy, M.A.,Stoddard, B.L.,Hicks, D.R. (deposition date: 2023-07-28, release date: 2024-12-11, Last modification date: 2026-07-08)

Primary citation

Hanna, S.,Salveson, P.J.,Wicky, B.,Kennedy, M.A.,Hicks, D.R.,Moller, C.,Cheng, S.,Li, X.,Abedi, M.,Coventry, B.,Said, M.Y.,Bera, A.K.,Kang, A.,Stoddard, B.L.,Baker, D.
De novo design of a macrocycle-induced dimerization system for cellular control.
Nat Commun, 2026

PubMed 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 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.

PubMed: 42151133
DOI: 10.1038/s41467-026-71345-8

Experimental method

X-RAY DIFFRACTION (2.05 Å)