9dop
From Proteopedia
Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca2+ dependent allosteric binding site
Structural highlights
DiseasePADI4_HUMAN Genetic variations in PADI4 are a cause of susceptibility to rheumatoid arthritis (RA) [MIM:180300. It is a systemic inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Note=Could have an important role in the pathogenesis of rheumatoid arthritis by increasing citrullination of proteins in rheumatoid arthritis synovial tissues, leading, in a cytokine-rich milieu, to a break in tolerance to citrullinated peptides processed and presented in the appropriate HLA context.[1] FunctionPADI4_HUMAN Catalyzes the citrullination/deimination of arginine residues of proteins. Citrullinates histone H3 at 'Arg-8' and/or 'Arg-17' and histone H4 at 'Arg-3', which prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription. Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1.[2] [3] Publication Abstract from PubMedPeptidylarginine 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. Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca(2+) dependent allosteric binding site.,Dakin LA, Xing L, Hall J, Ding W, Vajdos FF, Pelker JW, Ramsey S, Balbo P, Sahasrabudhe PV, Banker ME, Choi WY, Wright SW, Chang JS, Curto JM, Davoren JE, Drozda SE, Fennell KF, Futatsugi K, Kortum S, Lee KL, Liu S, Lovering F, Nicki JA, Trujillo JI, Vincent F, Schnute ME Nat Commun. 2025 May 16;16(1):4579. doi: 10.1038/s41467-025-59919-4. PMID:40379660[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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