Current research

Origin of Life
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.

Peptides with Special Modifications
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.

Peptide Selection Technologies (Akira Wada)
Based on the molecular evolution of peptides, we have designed and developed in vitro technologies for selecting new peptides that can bind to target molecules of interest. In the process of implementing the technologies, a wide variety of ribosomal complexes were synthesized using cell-free translation system to link 1012 types of peptides and their corresponding mRNAs. Subsequently, several peptides displayed on the complexes were specifically selected through affinity interactions with target molecules. Finally, target-binding peptides were newly identified by analyzing their mRNAs isolated from the selected complexes. Currently, we aim to create artificially functional peptides as drug candidates using the advanced technologies.