Yokohama City University

Principal Investigator_M.Sato

X-ray analyses and structural biology of post-translational modification enzymes

Mamoru Sato
Professor, Macromolecular Crystallography
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Our Aim

Based on the three-dimensional structures of posttranslationally modified enzymes determined by X-ray diffraction, we design potent inactivators of the enzymes for developing drugs that treat diseases caused by abnormal post-translational modifications.

Background

Protein arginine citrullination is a novel post-translational modification recognized by rheumatoid arthritis-specific autoantibodies. Inactivators of this modification enzyme are therefore expected to be drugs that treat autoimmune diseases such as rheumatoid arthritis.

Research Overview

One of the enzymes that citrullinate protein arginine residues, peptidyl-arginine deiminase type 4 (PAD4), is generally associated with development of rheumatoid arthritis. In this project, we designed potent PAD4 inactivators based on the active site structure of the enzyme to investigate the relationship with rheumatoid arthritis, and developed PAD4- inhibiting drugs to treat rheumatoid arthritis.

Achievements

We have determined the crystal structures of human wildtype PAD4 and an inactive mutant with various substrates by X-ray diffraction. Furthermore, we have chemically synthesized several PAD4 inactivators based on the active site structure of the enzyme and subjected these compounds to X-ray crystallographic analyses of the PAD4- inactivator complexes in order to elucidate the inhibitory mechanisms of the enzyme.