PDBsum entry 4qg9

Transferase

PDB id: 4qg9

Contents

Protein chains

499 a.a.

417 a.a.

Ligands

ACT ×4

Metals

_MG ×3

Waters ×448

References listed in PDB file

Key reference

• Title: Structural insight into mechanisms for dynamic regulation of pkm2.
• Authors: P.Wang, C.Sun, T.Zhu, Y.Xu.
• Ref.: Protein Cell, 2015, 6, 275-287. [DOI no: 10.1007/s13238-015-0132-x]
• PubMed id: 25645022

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.