Structure-based drug development
In our laboratory, we screened chemical compounds and identified the hit compounds (cpd) that can modulate CcO activity. We have successfully determined the structure of CcO-cpd complex, including allosteric activators and inhibitors. Structural information will lead us to elucidate the regulatory mechanism of CcO activity in combination with molecular dynamics and spectroscopic analysis.
Also, the structural information of Cco-cpd complex give us insight into the binding site, binding surface, and molecular interaction, thereby enable us to rationally design a better compound with higher affinity and better specificity.
Antibiotics targeting electron transfer chain
It is of great importance to prepare threat from antimicrobial resistant bacteria that currently spread worldwide. To this end, there is pressing need to develop an antibiotic with a novel mechanism of action. Respiratory chain is composed of multiple membrane protein complex, which has a fundamental machinery conserved in not only animals but also microbes. Until recently, this fundamental energy production machinery has not been a target for antibiotics development, however, cumulative progress made in the field of membrane protein structural analysis completely changed the idea.
Origin of mitochondria is symbiosis of alpha proteobacteria that had respiratory chain within an archaea cell. It is no wonder that the core structures of respiratory chain enzyme complex are conserved among eukaryotes and bacteria. However, mitochondrial cytochrome c oxidase has additional helices outside the core subunit, which suggest that they are similar but distinct. Based on this idea and structural information, we are currently working on the development of novel antibiotics that specifically target the electron transfer chain of pathogenic bacteria.