Surpassing the Limits of Existing Theory, Expanding Cryo-EM Applications to Small Protein Drug Interaction Analysis 

Professor KIM Dong-young’s Research Team Collaborates with Drug Discovery Platform Company Baobab AiBIO

Featured by Science and Published in Nature Communications

[May 6, 2026] 

<(Left) First author Dr. PARK Geon-woong, (Right) Cryo-EM structure of the approximately 32 kDa Human PLK1–onvansertib complex>

 “Too small to see?”

A research team led by Professor KIM Dong-young from YU’s School of Pharmacy (President CHOI Oe-chool) has, for the first time in the world, successfully identified the structure of ultramicroscopic proteins previously considered too small to be analyzed using cryogenic electron microscopy (Cryo-EM).

 Proteins are essential biological molecules responsible for a wide range of functions in the human body, and their structures provide critical information that determines those functions. Research aimed at accurately identifying protein structures forms the foundation for uncovering disease mechanisms and developing new drugs.

 Until now, X-ray crystallography, which utilizes high-intensity X-rays, has been the most widely used technique for protein structure analysis. This method determines protein structures by crystallizing proteins and exposing them to X-rays. However, it has significant experimental limitations because protein crystallization is often difficult, time-consuming, and labor-intensive. To overcome these challenges, Cryo-EM, which analyzes structures by collecting images of samples, has gained increasing attention and has recently become a core technology in protein structural analysis due to major advances in imaging resolution.

 Cryo-EM has generally been considered highly effective for analyzing large proteins exceeding 200 kDa (a unit used to indicate protein size), but limited in its ability to resolve smaller proteins. According to a theory proposed by 2017 Nobel Prize winner in Chemistry Richard Henderson, the minimum protein size theoretically analyzable by electron microscopy was approximately 38 kDa. In practice, the smallest Cryo-EM structure reported to date had been around 46 kDa, making 38 kDa widely regarded as the practical lower limit.

In this study, the research team successfully determined the structure of maltose-binding protein bound to maltose (a type of sugar), measuring approximately 41 kDa, at a resolution of 2.4 Å (angstroms, equal to 10⁻¹⁰ meters or 0.1 nm) using Cryo-EM. Furthermore, the team succeeded in resolving the structure of PLK1 (approximately 32 kDa) bound to the targeted anticancer drug onvansertib at a resolution of 3.4 Å. This achievement surpasses previously accepted theoretical limits and demonstrates that Cryo-EM can be used not only to determine the structures of small proteins, but also to analyze their interactions with drugs.

 Professor KIM Dong-young stated, “This study demonstrated that currently commercialized Cryo-EM instruments are capable of analyzing small protein structures beyond previously established theoretical limits. More importantly, we proved that the technology can precisely identify drug-binding states, significantly expanding the application range of Cryo-EM.” He added, “The findings also highlight the importance of cultivating highly skilled professional researchers alongside advances in instrumentation.”

 The study utilized Cryo-EM equipment provided by Baobab AiBIO (CEO NOH Kyung-tae), a drug discovery platform company, and was led by Dr. Park Geon-woong (Ph.D. graduate of YU’s Graduate School of Pharmacy and first author of the paper). A preprint version of the study released on bioRxiv in July last year attracted international attention after being featured on the official blog of Science. The revised paper was subsequently published online on April 14 in the international journal Nature Communications.