PDBsum entry 4n4t

Transferase/transferase inhibitor

PDB id: 4n4t

Contents

Protein chains

212 a.a.

199 a.a.

Ligands

2GV ×2

Metals

_ZN ×2

Waters ×141

PDB id:

4n4t

Name:

Transferase/transferase inhibitor

Title:

Co-crystal structure of tankyrase 1 with compound 3 [(4s)-3-{4-[6- amino-5-(pyrimidin-2-yl)pyridin-3-yl]phenyl}-5,5-dimethyl-4-phenyl-1, 3-oxazolidin-2-one]

Structure:

Tankyrase-1. Chain: a, b. Fragment: unp residues 1104-1314. Synonym: tank1, adp-ribosyltransferase diphtheria toxin-like 5, artd5, trf1-interacting ankyrin-related adp-ribose polymerase 1, tankyrase i. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: tnks, tnks1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.32Å R-factor: 0.251 R-free: 0.275

Authors:

X.Huang

Key ref:

H.Huang et al. (2013). Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors. Acs Med Chem Lett, 4, 1218-1223. PubMed id: 24900633 DOI: 10.1021/ml4003315

Date:

08-Oct-13 Release date: 11-Dec-13

Protein chain

Q6PFX9  (TNKS1_MOUSE) -  Poly [ADP-ribose] polymerase tankyrase-1 from Mus musculus

Seq: 1320 a.a.

Struc: 212 a.a.*

Protein chain

Q6PFX9  (TNKS1_MOUSE) -  Poly [ADP-ribose] polymerase tankyrase-1 from Mus musculus

Seq: 1320 a.a.

Struc: 199 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chains A, B: E.C.2.4.2.- - ?????
• Enzyme class 2: Chains A, B: 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/ml4003315

Acs Med Chem Lett 4:1218-1223 (2013)

PubMed id: 24900633

Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors.

H.Huang, A.Guzman-Perez, L.Acquaviva, V.Berry, H.Bregman, J.Dovey, H.Gunaydin, X.Huang, L.Huang, D.Saffran, R.Serafino, S.Schneider, C.Wilson, E.F.DiMauro.

ABSTRACT

Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors. These compounds exhibited good enzyme and cell potency as well as selectivity over other PARP isoforms. Co-crystal structures of these 2-aminopyridine oxazolidinones complexed to TNKS reveal an induced-pocket binding mode that does not involve interactions with the nicotinamide binding pocket. Oral dosing of lead compounds 3 and 4 resulted in significant effects on several Wnt-pathway biomarkers in a three day DLD-1 mouse tumor PD model.