8T2J

Structure of the catalytic domain of PPM1D/Wip1 serine/threonine phosphatase

8T2J の概要

• エントリーDOI: 10.2210/pdb8t2j/pdb
• 分子名称: Protein phosphatase 1D, MAGNESIUM ION, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• 機能のキーワード: protein phosphatase, metal-binding protein, cell cycle, cancer, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38600.38

構造登録者

Kumar, J.P.,Kosek, D.,Dyda, F. (登録日: 2023-06-06, 公開日: 2024-06-12, 最終更新日: 2024-10-23)

主引用文献

Kumar, J.P.,Kosek, D.,Durell, S.R.,Miller Jenkins, L.M.,Debnath, S.,Coussens, N.P.,Hall, M.D.,Appella, D.H.,Dyda, F.,Mazur, S.J.,Appella, E.
Crystal structure and mechanistic studies of the PPM1D serine/threonine phosphatase catalytic domain.
J.Biol.Chem., 300:107561-107561, 2024

PubMed Abstract: Protein phosphatase 1D (PPM1D, Wip1) is induced by the tumor suppressor p53 during DNA damage response signaling and acts as an oncoprotein in several human cancers. Although PPM1D is a potential therapeutic target, insights into its atomic structure were challenging due to flexible regions unique to this family member. Here, we report the first crystal structure of the PPM1D catalytic domain to 1.8 Å resolution. The structure reveals the active site with two Mg ions bound, similar to other structures. The flap subdomain and B-loop, which are crucial for substrate recognition and catalysis, were also resolved, with the flap forming two short helices and three short β-strands that are followed by an irregular loop. Unexpectedly, a nitrogen-oxygen-sulfur bridge was identified in the catalytic domain. Molecular dynamics simulations and kinetic studies provided further mechanistic insights into the regulation of PPM1D catalytic activity. In particular, the kinetic experiments demonstrated a magnesium concentration-dependent lag in PPM1D attaining steady-state velocity, a feature of hysteretic enzymes that show slow transitions compared with catalytic turnover. All combined, these results advance the understanding of PPM1D function and will support the development of PPM1D-targeted therapeutics.

PubMed: 39002674
DOI: 10.1016/j.jbc.2024.107561

実験手法

X-RAY DIFFRACTION (1.8 Å)