Author
Listed:
- Leslie A. Dakin
(Pfizer Inc)
- Li Xing
(Pfizer Inc)
- Justin Hall
(Pfizer Inc)
- Weidong Ding
(Pfizer Inc)
- Felix F. Vajdos
(Pfizer Inc)
- Jeffrey W. Pelker
(Pfizer Inc)
- Simeon Ramsey
(Pfizer Inc)
- Paul Balbo
(Pfizer Inc)
- Parag V. Sahasrabudhe
(Pfizer Inc)
- Mary Ellen Banker
(Pfizer Inc)
- Won Young Choi
(Pfizer Inc)
- Stephen W. Wright
(Pfizer Inc)
- Jeanne S. Chang
(Pfizer Inc)
- John M. Curto
(Pfizer Inc)
- Jennifer E. Davoren
(Pfizer Inc)
- Susan E. Drozda
(Pfizer Inc)
- Kimberly F. Fennell
(Pfizer Inc)
- Kentaro Futatsugi
(Pfizer Inc)
- Steve Kortum
(Pfizer Inc)
- Katherine L. Lee
(Pfizer Inc)
- Shenping Liu
(Pfizer Inc)
- Frank Lovering
(Pfizer Inc)
- Jennifer A. Nicki
(Pfizer Inc)
- John I. Trujillo
(Pfizer Inc)
- Fabien Vincent
(Pfizer Inc)
- Mark E. Schnute
(Pfizer Inc)
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.
Suggested Citation
Leslie A. Dakin & Li Xing & Justin Hall & Weidong Ding & Felix F. Vajdos & Jeffrey W. Pelker & Simeon Ramsey & Paul Balbo & Parag V. Sahasrabudhe & Mary Ellen Banker & Won Young Choi & Stephen W. Wrig, 2025.
"Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca2+ dependent allosteric binding site,"
Nature Communications, Nature, vol. 16(1), pages 1-12, December.
Handle:
RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59919-4
DOI: 10.1038/s41467-025-59919-4
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