PDBsum entry 4b2d

Transferase

PDB id: 4b2d

Contents

Protein chain

518 a.a.

Ligands

SER ×4

FBP ×4

Metals

_MG ×2

Waters ×1243

PDB id:

4b2d

Name:

Transferase

Title:

Human pkm2 with l-serine and fbp bound.

Structure:

Pyruvate kinase isozymes m1/m2. Chain: a, b, c. Synonym: pyruvate kinase m2, cytosolic thyroid hormone-binding protein cthbp, opa-interacting protein 3, oip-3, pyruvate kinase 2/3, pyruvate kinase muscle isozyme, thyroid hormone-binding protein 1, thbp1, tumor m2-pk, p58. Engineered: yes. Pyruvate kinase isozymes m1/m2. Chain: d.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.30Å R-factor: 0.176 R-free: 0.226

Authors:

B.Chaneton,P.Hillmann,L.Zheng,A.C.L.Martin,O.D.K.Maddocks, A.Chokkathukalam,J.E.Coyle,A.Jankevics,F.P.Holding,K.H.Vousden, C.Frezza,M.O'Reilly,E.Gottlieb

Key ref:

B.Chaneton et al. (2012). Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature, 491, 458-462. PubMed id: 23064226

Date:

13-Jul-12 Release date: 10-Oct-12

Protein chains

P14618  (KPYM_HUMAN) -  Pyruvate kinase PKM from Homo sapiens

Seq: 531 a.a.

Struc: 518 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.7.1.40 - pyruvate kinase.
• Reaction: pyruvate + ATP = phosphoenolpyruvate + ADP + H⁺

pyruvate + ATP (Bound ligand (Het Group name = SER) matches with 62.50% similarity) = phosphoenolpyruvate + ADP + H(+) (Bound ligand (Het Group name = FBP) matches with 42.86% similarity)

• Enzyme class 3: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺
• Enzyme class 4: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Nature 491:458-462 (2012)

PubMed id: 23064226

Serine is a natural ligand and allosteric activator of pyruvate kinase M2.

B.Chaneton, P.Hillmann, L.Zheng, A.C.Martin, O.D.Maddocks, A.Chokkathukalam, J.E.Coyle, A.Jankevics, F.P.Holding, K.H.Vousden, C.Frezza, M.O'Reilly, E.Gottlieb.

ABSTRACT

Cancer cells exhibit several unique metabolic phenotypes that are critical for cell growth and proliferation. Specifically, they overexpress the M2 isoform of the tightly regulated enzyme pyruvate kinase (PKM2), which controls glycolytic flux, and are highly dependent on de novo biosynthesis of serine and glycine. Here we describe a new rheostat-like mechanistic relationship between PKM2 activity and serine biosynthesis. We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. This reduction in PKM2 activity shifts cells to a fuel-efficient mode in which more pyruvate is diverted to the mitochondria and more glucose-derived carbon is channelled into serine biosynthesis to support cell proliferation.