Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca2+ dependent allosteric binding site
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. 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 ()
Additional contact information
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
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
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59919-4
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DOI: 10.1038/s41467-025-59919-4
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