Inhibitors and inactivators of Protein Arginine Deiminase 4: Functional and structural characterization

BIOL 232

Yuan Luo, luo@mail.chem.sc.edu1, Kyouhei Arita2, Monica Bhatia, bhatia@mail.chem.sc.edu1, Bryan Knuckley1, Young-Ho Lee3, Michael R. Stallcup3, Mamoru Sato2, and Paul R. Thompson, thompson@mail.chem.sc.edu1. (1) Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, SC 29208, (2) Graduate School of Integrated Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan, (3) Department of Biochemistry & Molecular Biology, University of Southern California, 1333 San Pablo Street, MCA 51A, Los Angeles, CA 90089
Protein arginine deiminase 4 (PAD4) is a Ca2+-dependent enzyme that catalyzes the post-translational modification of peptidyl arginine to citrulline and has been strongly implied to play important roles in transcriptional regulation and rheumatoid arthritis. Herein, we present the first crystal structure of wild-type PAD4 in complex with F3-amidine (1), a potent PAD4 inactivator that we have reported. This structure has confirmed the formation of a covalent bond between 1 and PAD4 and provided critical insights into inactivation mechanisms. We further report a new PAD4 inactivator, N-á-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (2, Cl3-amidine), which is significantly more potent than 1 and demonstrates in vivo PAD4-inhibiting activity in a mammalian cell line. 2 will also be a powerful chemical probe for studying in vivo functions of PAD4. The emergence of both compounds has addressed the lack of small molecular tools to study PAD4 whose importance is increasingly recognized by the scientific community.
 

Enzymes
4:30 PM-6:30 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Biological Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006