Designer Adaptor Proteins for Functional Conversion of Peptides to Small-Molecule Ligands toward In-Cell Catalytic Protein Modification.

Autor:	Fujimura A; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Ishida H; Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Nozaki T; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Terada S; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Azumaya Y; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Ishiguro T; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Kamimura YR; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Kujirai T; Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan., Kurumizaka H; Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan., Kono H; Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Yamatsugu K; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Kawashima SA; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Kanai M; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Jazyk:	angličtina
Zdroj:	ACS central science [ACS Cent Sci] 2023 Oct 25; Vol. 9 (11), pp. 2115-2128. Date of Electronic Publication: 2023 Oct 25 (Print Publication: 2023).
DOI:	10.1021/acscentsci.3c00930
Abstrakt:	Peptides are privileged ligands for diverse biomacromolecules, including proteins; however, their utility is often limited due to low membrane permeability and in-cell instability. Here, we report peptide ligand-inserted eDHFR (PLIED) fusion protein as a universal adaptor for targeting proteins of interest (POI) with cell-permeable and stable synthetic functional small molecules (SFSM). PLIED binds to POI through the peptide moiety, properly orienting its eDHFR moiety, which then recruits trimethoprim (TMP)-conjugated SFSM to POI. Using a lysine-acylating BAHA catalyst as SFSM, we demonstrate that POI (MDM2 and chromatin histone) are post-translationally and synthetically acetylated at specific lysine residues. The residue-selectivity is predictable in an atomic resolution from molecular dynamics simulations of the POI/PLIED/TMP-BAHA (MTX was used as a TMP model) ternary complex. This designer adaptor approach universally enables functional conversion of impermeable peptide ligands to permeable small-molecule ligands, thus expanding the in-cell toolbox of chemical biology. Competing Interests: The authors declare no competing financial interest. (© 2023 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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