9DOP
Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca2+ dependent allosteric binding site
This is a non-PDB format compatible entry.
Summary for 9DOP
| Entry DOI | 10.2210/pdb9dop/pdb |
| Related | 9DOL |
| Descriptor | Protein-arginine deiminase type-4, CALCIUM ION, (2R)-2-amino-2-{1-[(5M)-5-(3,5-dichloropyridin-2-yl)isoquinolin-1-yl]piperidin-4-yl}-1-(pyrrolidin-1-yl)ethan-1-one, ... (4 entities in total) |
| Functional Keywords | peptyl arginine deiminase, inhibitor, allosteric, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 75490.40 |
| Authors | |
| Primary citation | Dakin, L.A.,Xing, L.,Hall, J.,Ding, W.,Vajdos, F.F.,Pelker, J.W.,Ramsey, S.,Balbo, P.,Sahasrabudhe, P.V.,Banker, M.E.,Choi, W.Y.,Wright, S.W.,Chang, J.S.,Curto, J.M.,Davoren, J.E.,Drozda, S.E.,Fennell, K.F.,Futatsugi, K.,Kortum, S.,Lee, K.L.,Liu, S.,Lovering, F.,Nicki, J.A.,Trujillo, J.I.,Vincent, F.,Schnute, M.E. Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca 2+ dependent allosteric binding site. Nat Commun, 16:4579-4579, 2025 Cited by PubMed Abstract: Peptidylarginine deiminases (PAD1-4) are calcium dependent enzymes responsible for protein citrullination, a post-translational modification converting arginine residues to citrulline. Elevated levels of citrullinated proteins have been associated with rheumatoid arthritis, neurodegenerative diseases, and cancers. Though highly selective PAD4 inhibitors have been described, inhibitors to the broader family currently are limited to covalent substrate analogs. Herein, we describe an allosteric binding pocket common to PAD1-4 suitable for the identification of potent, non-covalent enzyme inhibitors. A ligand-based virtual screen is utilized to identify a PAD4 inhibitor for which surface plasmon resonance confirms target binding but non-competitively with a known PAD4 ligand. We further show through co-crystal structure analysis that the ligand binds PAD4 at an allosteric pocket resulting in stabilization of a catalytically inactive, calcium-deficient enzyme conformation. A ligand designed based on this site potently inhibits all four PAD isozymes and prevents protein citrullination in neutrophils with a broader protein repertoire than observed with a PAD4-selective inhibitor. PubMed: 40379660DOI: 10.1038/s41467-025-59919-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.44 Å) |
Structure validation
Download full validation report
