7POX

TNKS2 in complex with OM-1700, treated with H2O2

This is a non-PDB format compatible entry.

Summary for 7POX

• Entry DOI: 10.2210/pdb7pox/pdb
• Descriptor: Poly [ADP-ribose] polymerase tankyrase-2, N-[3-[5-(5-ethoxypyridin-2-yl)-4-(2-fluorophenyl)-1,2,4-triazol-3-yl]cyclobutyl]pyridine-2-carboxamide (3 entities in total)
• Functional Keywords: zinc, coordination, enzyme, poly-adp-ribosylation, inhibitor, h2o2, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 50573.16

Authors

Sowa, S.T.,Lehtio, L. (deposition date: 2021-09-10, release date: 2022-05-04, Last modification date: 2024-01-31)

Primary citation

Sowa, S.T.,Lehtio, L.
The zinc-binding motif in tankyrases is required for the structural integrity of the catalytic ADP-ribosyltransferase domain.
Open Biology, 12:210365-210365, 2022

PubMed Abstract: Tankyrases are ADP-ribosylating enzymes that regulate many physiological processes in the cell and are considered promising drug targets for cancer and fibrotic diseases. The catalytic ADP-ribosyltransferase domain of tankyrases contains a unique zinc-binding motif of unknown function. Recently, this motif was suggested to be involved in the catalytic activity of tankyrases. In this work, we set out to study the effect of the zinc-binding motif on the activity, stability and structure of human tankyrases. We generated mutants of human tankyrase (TNKS) 1 and TNKS2, abolishing the zinc-binding capabilities, and characterized the proteins biochemically and biophysically . We further generated a crystal structure of TNKS2, in which the zinc ion was oxidatively removed. Our work shows that the zinc-binding motif in tankyrases is a crucial structural element which is particularly important for the structural integrity of the acceptor site. While mutation of the motif rendered TNKS1 inactive, probably due to introduction of major structural defects, the TNKS2 mutant remained active and displayed an altered activity profile compared to the wild-type.

PubMed: 35317661
DOI: 10.1098/rsob.210365

Experimental method

X-RAY DIFFRACTION (2.5 Å)