PDBsum entry 4l31

Transferase/transferase inhibitor

PDB id: 4l31

Contents

Protein chains

161 a.a.

47 a.a.

Ligands

F08 ×2

SO4 ×4

GOL

Metals

_ZN ×2

Waters ×284

PDB id:

4l31

Name:

Transferase/transferase inhibitor

Title:

Tankyrase 2 in complex with methyl 4-(4-oxochromen-2-yl)benzoate

Structure:

Tankyrase-2. Chain: a, b. Fragment: c-terminal fragment, unp residues 946-1113. Synonym: tank2, adp-ribosyltransferase diphtheria toxin-like 6, artd6, poly [adp-ribose] polymerase 5b, tnks-2, trf1-interacting ankyrin-related adp-ribose polymerase 2, tankyrase ii, tankyrase-like protein, tankyrase-related protein. Engineered: yes. Tankyrase-2.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tnks2, parp5b, tank2, tnkl. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.00Å R-factor: 0.171 R-free: 0.216

Authors:

M.Narwal,T.Haikarainen,L.Lehtio

Key ref:

M.Narwal et al. (2013). Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity. J Med Chem, 56, 7880-7889. PubMed id: 24116873 DOI: 10.1021/jm401463y

Date:

05-Jun-13 Release date: 30-Oct-13

Protein chains

Q9H2K2  (TNKS2_HUMAN) -  Poly [ADP-ribose] polymerase tankyrase-2 from Homo sapiens

Seq: 1166 a.a.

Struc: 161 a.a.

Protein chains

Q9H2K2  (TNKS2_HUMAN) -  Poly [ADP-ribose] polymerase tankyrase-2 from Homo sapiens

Seq: 1166 a.a.

Struc: 47 a.a.

Enzyme reactions

• Enzyme class 2: Chains A, C, B, D: E.C.2.4.2.- - ?????
• Enzyme class 3: Chains A, C, B, D: E.C.2.4.2.30 - NAD(+) ADP-ribosyltransferase.

Pathway:

• Reaction: NAD⁺ + (ADP-D-ribosyl)n-acceptor = nicotinamide + (ADP-D- ribosyl)n+1-acceptor + 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

Added reference

DOI no: 10.1021/jm401463y

J Med Chem 56:7880-7889 (2013)

PubMed id: 24116873

Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity.

M.Narwal, J.Koivunen, T.Haikarainen, E.Obaji, O.E.Legala, H.Venkannagari, P.Joensuu, T.Pihlajaniemi, L.Lehtiö.

ABSTRACT

Tankyrases are ADP-ribosyltransferases that play key roles in various cellular pathways, including the regulation of cell proliferation, and thus, they are promising drug targets for the treatment of cancer. Flavones have been shown to inhibit tankyrases and we report here the discovery of more potent and selective flavone derivatives. Commercially available flavones with single substitutions were used for structure-activity relationship studies, and cocrystal structures of the 18 hit compounds were analyzed to explain their potency and selectivity. The most potent inhibitors were also tested in a cell-based assay, which demonstrated that they effectively antagonize Wnt signaling. To assess selectivity, they were further tested against a panel of homologous human ADP-ribosyltransferases. The most effective compound, 22 (MN-64), showed 6 nM potency against tankyrase 1, isoenzyme selectivity, and Wnt signaling inhibition. This work forms a basis for rational development of flavones as tankyrase inhibitors and guides the development of other structurally related inhibitors.