4RPP

crystal structure of PKM2-K422R mutant bound with FBP

4RPP の概要

• エントリーDOI: 10.2210/pdb4rpp/pdb
• 関連するPDBエントリー: 4QG6 4QG8 4QG9 4QGC
• 分子名称: Pyruvate kinase PKM, 1,6-di-O-phosphono-beta-D-fructofuranose (3 entities in total)
• 機能のキーワード: pkm2, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 234957.59

構造登録者

Wang, P.,Sun, C.,Zhu, T.,Xu, Y. (登録日: 2014-10-31, 公開日: 2015-02-25, 最終更新日: 2024-05-29)

主引用文献

Wang, P.,Sun, C.,Zhu, T.,Xu, Y.
Structural insight into mechanisms for dynamic regulation of PKM2.
Protein Cell, 6:275-287, 2015

PubMed Abstract: Pyruvate kinase isoform M2 (PKM2) converts phosphoenolpyruvate (PEP) to pyruvate and plays an important role in cancer metabolism. Here, we show that post-translational modifications and a patient-derived mutation regulate pyruvate kinase activity of PKM2 through modulating the conformation of the PKM2 tetramer. We determined crystal structures of human PKM2 mutants and proposed a "seesaw" model to illustrate conformational changes between an inactive T-state and an active R-state tetramers of PKM2. Biochemical and structural analyses demonstrate that PKM2(Y105E) (phosphorylation mimic of Y105) decreases pyruvate kinase activity by inhibiting FBP (fructose 1,6-bisphosphate)-induced R-state formation, and PKM2(K305Q) (acetylation mimic of K305) abolishes the activity by hindering tetramer formation. K422R, a patient-derived mutation of PKM2, favors a stable, inactive T-state tetramer because of strong intermolecular interactions. Our study reveals the mechanism for dynamic regulation of PKM2 by post-translational modifications and a patient-derived mutation and provides a structural basis for further investigation of other modifications and mutations of PKM2 yet to be discovered.

PubMed: 25645022
DOI: 10.1007/s13238-015-0132-x

実験手法

X-RAY DIFFRACTION (2.585 Å)