PDBsum entry 5x1v

Transferase

PDB id: 5x1v

Contents

Protein chains

512 a.a.

Ligands

FBP ×4

7XX ×4

Waters ×473

PDB id:

5x1v

Name:

Transferase

Title:

Pkm2 in complex with compound 2

Structure:

Pyruvate kinase pkm. Chain: a, b, c, d. Synonym: 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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pkm, oip3, pk2, pk3, pkm2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.10Å R-factor: 0.238 R-free: 0.274

Authors:

Y.Matsui,H.Hanzawa

Key ref:

Y.Matsui et al. (2017). Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator. Bioorg Med Chem, 25, 3540-3546. PubMed id: 28511909 DOI: 10.1016/j.bmc.2017.05.004

Date:

27-Jan-17 Release date: 31-May-17

Protein chains

P14618  (KPYM_HUMAN) -  Pyruvate kinase PKM from Homo sapiens

Seq: 531 a.a.

Struc: 512 a.a.

Enzyme reactions

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

pyruvate + ATP = 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

DOI no: 10.1016/j.bmc.2017.05.004

Bioorg Med Chem 25:3540-3546 (2017)

PubMed id: 28511909

Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator.

Y.Matsui, I.Yasumatsu, T.Asahi, T.Kitamura, K.Kanai, O.Ubukata, H.Hayasaka, S.Takaishi, H.Hanzawa, S.Katakura.

ABSTRACT

Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS). Among several hit compounds, a fragment-like hit compound with low potency but high ligand efficiency was identified. Two molecules of the hit compound bound at one activator binding site, and the molecules were linked based on the crystal structure. Since this linkage succeeded in maintaining the original position of the hit compound, the obtained compound exhibited highly improved potency in an in vitro assay. The linked compound also showed PKM2 activating activity in a cell based assay, and cellular growth inhibition of the A549 cancer cell line. Discovery of this novel scaffold and binding mode of the linked compound provides a valuable platform for the structure-guided design of PKM2 activators.