Hiroshi Matsuo, Ph.D.
- Center for Cancer Research
- National Cancer Institute
- Building 538, Room 148
- Frederick, MD 21702
- 301-228-4375
- hiroshi.matsuo@nih.gov
RESEARCH SUMMARY
Dr. Matsuo's research focuses on the structure and function of proteins and their interactions with DNA and RNA, employing advanced techniques such as NMR, X-ray crystallography, and cryo-electron microscopy (cryo-EM). His current work primarily aims to elucidate the structural basis of the single-stranded DNA cytosine deaminase activity of APOBEC3 proteins, which are crucial in limiting HIV-1 replication and tumorigenesis. APOBEC3G (A3G) induces mutations in the HIV-1 genome, thereby reducing viral infectivity, while APOBEC3A (A3A) and APOBEC3B (A3B) are major contributors to mutations in cancer cells. To date, Dr. Matsuo’s team has determined over 10 structures of APOBEC3 proteins (A3s) and their complexes with substrate ssDNA. His research has also revealed that a short single-stranded RNA is vital for the interaction between A3G and the HIV-1 virion infectivity factor (Vif). This structural insight has enabled the development of oligonucleotide-based inhibitors targeting A3A and antagonists designed to block the A3G-Vif interaction.
Areas of Expertise
Hiroshi Matsuo, Ph.D.
Research
Research Highlights
“Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G.” Kouno T, Shibata S, Shigematsu M, Hyun J, Kim TG, Matsuo H, Wolf M. Nature Communications. 2023;14(1):4037. PubMed PMID: 37419875; PubMed Central PMCID: PMCPMC10328928.
A3 proteins catalyze the deamination of cytidines, converting them into 2ʹ-deoxy uridines in single-stranded DNA. This activity plays a critical role in restricting HIV-1 infection, with APOBEC3G (A3G), APOBEC3F (A3F), and APOBEC3H (A3H) acting as host defenses, with A3G being the most potent in inducing hypermutations in the viral genome. In response, HIV has evolved the ‘virion infectivity factor’ (Vif) protein as a counter-defense mechanism. Vif exploits a host E3 ubiquitin ligase to ubiquitinate the A3 proteins, leading to their degradation by the proteasome. Previously, we discovered the presence of single-stranded RNA (ssRNA) in the A3G-NTD:Vif:CBFβ:EloBEloC (A3G-NTD:VCBC) complex. Building on this finding, Dr. Kouno continued to investigate the role of ssRNA and, in collaboration with Dr. Mathias Wolf at the Okinawa Institute of Science and Technology, recently determined the structure of the A3G:RNA:Vif:CBFβ complex using single-particle cryo-electron microscopy. The biophysical and structural insights into the A3G-RNA-Vif interaction have informed the design of RNA antagonists to block the A3G-Vif interaction.
- Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state.” Maiti A, Hedger AK, Myint W, Balachandran V, Watts JK, Schiffer CA, Matsuo H. Nature Communications. 2022-11-19. PMID: 36402773
Our A3:ssDNA co-crystal structures and prior biochemical characterization indicated that A3s bind longer oligonucleotides and extensive interactions are needed for activity and therefore inhibition. In addition, we solved a co-crystal structure of the active A3G catalytic domain bound to a DNA oligomer containing a 2ʹ-deoxy zebularine (dZ-ssDNA). This structure revealed a transition state of the deamination reaction and provided structural information that has guided our design of transition state analogue inhibitors. Guided by our co-crystal structures, we designed and generated dZ-ssDNA inhibitors of A3A. Our data indicate that the dZ-ssDNA inhibitors bind A3A with higher affinity and inhibit its activity (Ki < 1µM).
Publications
Mechanism for APOBEC3G catalytic exclusion of RNA and non-substrate DNA
Biography
Hiroshi Matsuo, Ph.D.
Dr. Hiroshi Matsuo earned his Ph.D. in 1994 from the Department of Chemistry at Osaka University. His doctoral research focused on determining the homo-dimeric structure of the Cro repressor protein, a transcription repressor from λ-phage, using nuclear magnetic resonance (NMR) spectroscopy. After completing his Ph.D., Dr. Matsuo moved to Boston, where he worked as a postdoctoral fellow in Dr. Gerhard Wagner’s lab at Harvard Medical School. There, he solved the structure of eukaryotic translation initiation factor 4E (eIF4E) from yeast, which was embedded in a detergent micelle, using NMR. In doing so, he developed new methodologies to optimize NMR experiments for high-molecular-weight biomolecules.
In 2010, Dr. Matsuo joined the University of Minnesota’s Department of Biochemistry, Molecular Biology & Biophysics (BMBB), where he eventually received tenure. His research there focused on the structure and function of bacteriophage phi29 pRNA, a key component of the DNA packaging motor, as well as the HIV-1 restriction factor APOBEC3G. He also served as Director of the BMBB graduate program for four years.
In 2015, Dr. Matsuo joined the Basic Research Program at the Frederick National Laboratory for Cancer Research (FNLCR).
Job Vacancies
We have no open positions in our group at this time, please check back later.
To see all available positions at CCR, take a look at our Careers page. You can also subscribe to receive CCR's latest job and training opportunities in your inbox.
Team
News
Learn more about CCR research advances, new discoveries and more
on our news section.