4PNQ

Crystal Structure of human Tankyrase 2 in complex with 5AIQ.

Summary for 4PNQ

• Entry DOI: 10.2210/pdb4pnq/pdb
• Related: 4PML 4PNL 4PNM 4PNN 4PNR 4PNS 4PNT 4TJU 4TJW 4TJY 4TK0 4TK5 4TKF 4TKG 4TKI
• Descriptor: Tankyrase-2, ZINC ION, 5-aminoisoquinolin-1(4H)-one, ... (5 entities in total)
• Functional Keywords: poly(adp-ribosylation) polymerase (parp), transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q9H2K2
• Total number of polymer chains: 4
• Total formula weight: 104747.41

Authors

Qiu, W.,Lam, R.,Romanov, V.,Gordon, R.,Gebremeskel, S.,Vodsedalek, J.,Thompson, C.,Beletskaya, I.,Battaile, K.P.,Pai, E.F.,Chirgadze, N.Y. (deposition date: 2014-05-24, release date: 2014-10-15, Last modification date: 2023-12-27)

Primary citation

Qiu, W.,Lam, R.,Voytyuk, O.,Romanov, V.,Gordon, R.,Gebremeskel, S.,Vodsedalek, J.,Thompson, C.,Beletskaya, I.,Battaile, K.P.,Pai, E.F.,Rottapel, R.,Chirgadze, N.Y.
Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2.
Acta Crystallogr.,Sect.D, 70:2740-2753, 2014

PubMed Abstract: The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated β-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors.

PubMed: 25286857
DOI: 10.1107/S1399004714017660

Experimental method

X-RAY DIFFRACTION (1.85 Å)