 Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca2+ dependent allosteric binding siteLeslie 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. Wright,
Jeanne S. Chang,
John M. Curto,
Jennifer E. Davoren,
Susan E. Drozda,
Kimberly F. Fennell,
Kentaro Futatsugi,
Steve Kortum,
Katherine L. Lee,
Shenping Liu,
Frank Lovering,
Jennifer A. Nicki,
John I. Trujillo,
Fabien Vincent and
Mark E. Schnute ()
Nature Communications, 2025, vol. 16, issue 1, 1-12 Abstract: 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. Date: 2025 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59919-4 Ordering information: This journal article can be ordered from DOI: 10.1038/s41467-025-59919-4 Access Statistics for this article Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie More articles in Nature Communications from Nature |
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