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RNA polymerase III (Pol III) is a vital molecular machine that every eukaryotic cell uses to produce short but essential RNA molecules needed to make proteins and sustain life. However, one of its key domain in Rpc34 subunit, has evaded detection by conventional structural biology methods including cryo-EM because of its being highly mobile. A research team led by Dr. Wei-Hau Chang (Institute of Chemistry), Dr. Hung-Ta Chen (Institute of Molecular Biology), together with Dr. I-Ping Tu (Institute of Statistical Science) at Academia Sinica innovated a new labeling method based on Bertozzi click chemistry and developed efficient and accurate FRET data analysis to allow them to track this tiny Rpc34 winged-helix domain in real time, one molecule at a time. They discovered that this domain moves among three preferred positions, helping keeping the transcription machinery stable and prime the machine ready for quickly start a new round of RNA production. Beyond deepening our understanding of how Pol III works, the new labeling technique provides a powerful tool for studying the dynamics of functional parts in many large biological machines. The research has been published on June 29, 2026 in PNAS. The research was supported by Academia Sinica and the National Science and Technology Council (NSTC).