8DWK

Inhibitor-3:PP1 reconstituted complex

8DWK の概要

• エントリーDOI: 10.2210/pdb8dwk/pdb
• 分子名称: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit, E3 ubiquitin-protein ligase PPP1R11, MANGANESE (II) ION, ... (4 entities in total)
• 機能のキーワード: inhibitor-3, protein phosphatase 1, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 79278.66

構造登録者

Choy, M.S.,Srivastava, G.,Page, R.,Peti, W. (登録日: 2022-08-01, 公開日: 2023-02-15, 最終更新日: 2023-10-25)

主引用文献

Srivastava, G.,Choy, M.S.,Bolik-Coulon, N.,Page, R.,Peti, W.
Inhibitor-3 inhibits Protein Phosphatase 1 via a metal binding dynamic protein-protein interaction.
Nat Commun, 14:1798-1798, 2023

PubMed Abstract: To achieve substrate specificity, protein phosphate 1 (PP1) forms holoenzymes with hundreds of regulatory and inhibitory proteins. Inhibitor-3 (I3) is an ancient inhibitor of PP1 with putative roles in PP1 maturation and the regulation of PP1 activity. Here, we show that I3 residues 27-68 are necessary and sufficient for PP1 binding and inhibition. In addition to a canonical RVxF motif, which is shared by nearly all PP1 regulators and inhibitors, and a non-canonical SILK motif, I3 also binds PP1 via multiple basic residues that bind directly in the PP1 acidic substrate binding groove, an interaction that provides a blueprint for how substrates bind this groove for dephosphorylation. Unexpectedly, this interaction positions a CCC (cys-cys-cys) motif to bind directly across the PP1 active site. Using biophysical and inhibition assays, we show that the I3 CCC motif binds and inhibits PP1 in an unexpected dynamic, fuzzy manner, via transient engagement of the PP1 active site metals. Together, these data not only provide fundamental insights into the mechanisms by which IDP protein regulators of PP1 achieve inhibition, but also shows that fuzzy interactions between IDPs and their folded binding partners, in addition to enhancing binding affinity, can also directly regulate enzyme activity.

PubMed: 37002212
DOI: 10.1038/s41467-023-37372-5

実験手法

X-RAY DIFFRACTION (2.5 Å)