4QG8

crystal structure of PKM2-K305Q mutant

Summary for 4QG8

• Entry DOI: 10.2210/pdb4qg8/pdb
• Related: 4QG6 4QG9 4QGC 4RPP
• Descriptor: Pyruvate kinase PKM, MAGNESIUM ION, POTASSIUM ION, ... (6 entities in total)
• Functional Keywords: tetramer, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14618
• Total number of polymer chains: 4
• Total formula weight: 233844.85

Authors

Wang, P.,Sun, C.,Zhu, T.,Xu, Y. (deposition date: 2014-05-22, release date: 2015-02-25, Last modification date: 2024-05-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)