Proteins are the workhorses of the cell, performing a variety of functions such as catalyzing chemical reactions, transmitting signals, and providing structural support. The specific function of a protein is largely determined by its three-dimensional shape; structure.

X-ray crystallography is a powerful tool used by scientists to determine the three-dimensional structure of proteins at atomic resolution. By examining the structure of a protein, we can gain insights into its mechanisms of action and identify potential targets for drug development. 

Faithful transfer of genetic data is crucial to all living organisms. RNA polymerase II utilizes DNA as a template to produce messenger RNA (mRNA) which called transcription. During transcription, elongation complex encounters a wide-variety of DNA lesions/modifications or DNA binding molecules, such as oxidative DNA damage, epigenetic DNA modifications, DNA adduct from anticancer agents, or chromosome structure (nucleosome).

We strive to unravel the intricate interactions between RNA polymerase and the DNA template during transcription elongation, and to uncover the structural basis of transcriptional regulation. 

In vitro transcription (IVT) is a DNA-templated process for synthesizing long RNA transcripts, including messenger RNA (mRNA), using bacteriophage T7 RNA polymerase (T7 RNAP). While T7 RNAP can produce full-length RNA transcripts with high fidelity, it can also generate immunostimulatory byproducts like double-stranded RNA that require complex purification methods for safe and effective mRNA-based therapies. Furthermore, to increase therapeutic efficacy and overcome inherent immunogenicity, modified nucleobase N1-methyl-pseudouridine (m1Ψ) is incorporated in the COVID-19 mRNA vaccine. Therefore, understanding the interaction of T7 RNAP or its mutants with various unnatural nucleotides is crucial for the development of potential RNA therapeutics.

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has an RNA genome that is replicated and transcribed by its RNA dependent RNA polymerase (RdRp). As RdRp plays a critical role in both transcription and replication, it is a prime target for drug development against COVID-19. Our lab is particularly interested in studying potential RdRp inhibitors, especially targeting transcription elongation. By investigating the molecular mechanisms of transcription blockage by approved drugs and the viral mutagenesis that can lead to drug resistance, we aim to contribute to the development of new therapeutics not only for COVID-19 but also for other viral diseases.