8SML

hPAD4 bound to inhibitory Fab hI365

8SML の概要

• エントリーDOI: 10.2210/pdb8sml/pdb
• EMDBエントリー: 40590
• 分子名称: Protein-arginine deiminase type-4, Fab hI365 light chain, Fab hI365 heavy chain, ... (4 entities in total)
• 機能のキーワード: complex, deiminase, enzyme, arginine, inflammation, calcium binding, fab, immune system, hydrolase-immune system complex, hydrolase/immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 251592.69

構造登録者

Maker, A.,Verba, K.A. (登録日: 2023-04-26, 公開日: 2024-03-06, 最終更新日: 2024-06-12)

主引用文献

Zhou, X.,Kong, S.,Maker, A.,Remesh, S.G.,Leung, K.K.,Verba, K.A.,Wells, J.A.
Antibody discovery identifies regulatory mechanisms of protein arginine deiminase 4.
Nat.Chem.Biol., 20:742-750, 2024

PubMed Abstract: 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.

PubMed: 38308046
DOI: 10.1038/s41589-023-01535-8

実験手法

ELECTRON MICROSCOPY (3.3 Å)