Area of interest
Our research focuses on the structure and function of medically important proteins from the crystallographic approach. The current topics include cyclophilin, calcineurin, heat shock protein 90 (Hsp90), and cyclic nucleotide phosphodiesterase.
Cyclophilin (CyP) is a binding protein for the immunosuppressive drug cyclosporin A (CsA) and also an enzyme catalyzing the cis-trans isomerization of a peptidyl-prolyl bond. The CyP-CsA complex binds calcineurin, a calmodulin-dependent serine/threonine protein phosphatase in signal transduction pathway towards T-cell activation. Cyclophilin has been reported to be involved in protein folding and to function as a molecular chaperone in several biological systems. Cyclophilin 40 is a member of the Hsp90 molecular chaperone system that regulates many biological processes such as the steroid hormone signaling pathway. In addition, cyclophilin binds the HIV-1 capsid protein and is required for HIV-1 infectivity. Our crystal structures of CyP, its complexes with CsA and the HIV peptide, and the CyP-calcineurin complex have provided insight into the mechanism of the cis-trans isomerization, the regulation of HIV-1 activity by CyP, and the signal transduction towards T-cell activation.
Cyclic nucleotide phosphodiesterase (PDE) hydrolyzes adenosine or guanosine 3',5'-cyclic phosphate (cAMP or cGMP) to 5'-AMP and 5?-GMP. Selective PDE inhibitors towards a certain family of PDEs have been widely studied as therapeutic agents. For example, the PDE5 inhibitor sildenafil (VIAGRA) is a prescription drug for erectile dysfunction of male patients and PDE3 inhibitor cilostamide is a drug for heart disease. Our structural studies on PDE4 and PDE5 have provided insight into the inhibitor selectivity of the PDE families and a guideline for development of new drugs for various human diseases.