Antibody discovery identifies regulatory mechanisms of protein arginine deiminase 4.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
02 Feb 2024
02 Feb 2024
Historique:
received:
06
04
2023
accepted:
20
12
2023
medline:
3
2
2024
pubmed:
3
2
2024
entrez:
2
2
2024
Statut:
aheadofprint
Résumé
Unlocking the potential of protein arginine deiminase 4 (PAD4) as a drug target for rheumatoid arthritis requires a deeper understanding of its regulation. In this study, we use unbiased antibody selections to identify functional antibodies capable of either activating or inhibiting PAD4 activity. Through cryogenic-electron microscopy, we characterized the structures of these antibodies in complex with PAD4 and revealed insights into their mechanisms of action. Rather than steric occlusion of the substrate-binding catalytic pocket, the antibodies modulate PAD4 activity through interactions with allosteric binding sites adjacent to the catalytic pocket. These binding events lead to either alteration of the active site conformation or the enzyme oligomeric state, resulting in modulation of PAD4 activity. Our study uses antibody engineering to reveal new mechanisms for enzyme regulation and highlights the potential of using PAD4 agonist and antagonist antibodies for studying PAD4-dependency in disease models and future therapeutic development.
Identifiants
pubmed: 38308046
doi: 10.1038/s41589-023-01535-8
pii: 10.1038/s41589-023-01535-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : 1P41CA1962 76
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : CA191018
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : GM097316
Organisme : Damon Runyon Cancer Research Foundation (Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation)
ID : DRG-665 2297-17
Organisme : Damon Runyon Cancer Research Foundation (Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation)
ID : (DFS-52-22
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)
ID : K99EB030587
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)
ID : R00EB030587
Informations de copyright
© 2024. The Author(s).
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