Laboratory for Advanced Biomolecular Engineering

Our team aims to engineer functional bio-macromolecules applicable to medical and basic biological research, by integrating technologies in synthetic and structural biology including in vitro evolution of protein/RNA, X-ray crystallography, and structure-based protein engineering.

Modified and cyclized peptides are promising scaffolds for next-generation drug discovery due to their high stability and specificity. Lasso peptides are bacterial antibiotic peptides characterized by a unique threaded rotaxane structure formed through the coordinated action of the maturation proteins B1, B2, and C, although the mechanism of this process has remained unclear. To elucidate the lasso peptide maturation process, we determined the crystal structure of the B1 protein complexed with the precursor peptide. We further performed rapid mutational analysis of B2 using a cell-free translation system combined with structure predictions by AI, identifying a critical hydrophobic interaction surface with B1. Finally, we demonstrated the biomedical potential of lasso peptides by developing a PET imaging probe based on an engineered lasso peptide.

We are also trying to experimentally reconstruct evolutionary pathway from primordial peptides to elaborate proteins. How life emerged from simple non-living chemistry on Earth remains one of the central questions in biology. Modern life relies on the mutual synthesis of proteins (RNA polymerases) and RNA (ribosomes), yet both are large molecular complexes whose origins are poorly understood. To address this question, we are reconstructing evolutionary intermediates between simple peptides and modern RNA polymerases. So far, we showed that self-organizing peptides can adsorb and concentrate RNA, reconstructed the core fold of RNA polymerase using peptides composed of only seven amino acid types, and identified unusually simple RNA polymerases from thermophilic bacteriophages. Furthermore, we demonstrated that simple mutations in the core fold of RNA polymerase can generate protein folds conserved in ribosomal proteins, providing insight into early protein fold diversification.