skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2

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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [1]
  1. Univ. Health Network, Toronto, ON (Canada)
  2. Univ. Health Network, Ontario (Canada); Univ. of Toronto, Toronto, ON (Canada)
  3. Univ. Health Network, Toronto, ON (Canada); Univ. of Toronto, Toronto, ON (Canada)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1162303
Grant/Contract Number:
AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Acta Crystallographica. Section D: Biological Crystallography (Online)
Additional Journal Information:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography (Online); Journal Volume: 70; Journal Issue: 10; Journal ID: ISSN 1399-0047
Publisher:
International Union of Crystallography
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; cancer; poly(ADP-ribose) polymerase; TNKS2; structure-based drug discovery; structural biology

Citation Formats

Qiu, Wei, Lam, Robert, Voytyuk, Oleksandr, Romanov, Vladimir, Gordon, Roni, Gebremeskel, Simon, Vodsedalek, Jakub, Thompson, Christine, Beletskaya, Irina, Battaile, Kevin P., Pai, Emil F., Rottapel, Robert, and Chirgadze, Nickolay Y. Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2. United States: N. p., 2014. Web. doi:10.1107/S1399004714017660.
Qiu, Wei, Lam, Robert, Voytyuk, Oleksandr, Romanov, Vladimir, Gordon, Roni, Gebremeskel, Simon, Vodsedalek, Jakub, Thompson, Christine, Beletskaya, Irina, Battaile, Kevin P., Pai, Emil F., Rottapel, Robert, & Chirgadze, Nickolay Y. Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2. United States. doi:10.1107/S1399004714017660.
Qiu, Wei, Lam, Robert, Voytyuk, Oleksandr, Romanov, Vladimir, Gordon, Roni, Gebremeskel, Simon, Vodsedalek, Jakub, Thompson, Christine, Beletskaya, Irina, Battaile, Kevin P., Pai, Emil F., Rottapel, Robert, and Chirgadze, Nickolay Y. Thu . "Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2". United States. doi:10.1107/S1399004714017660. https://www.osti.gov/servlets/purl/1162303.
@article{osti_1162303,
title = {Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2},
author = {Qiu, Wei and Lam, Robert and Voytyuk, Oleksandr and Romanov, Vladimir and Gordon, Roni and Gebremeskel, Simon and Vodsedalek, Jakub and Thompson, Christine and Beletskaya, Irina and Battaile, Kevin P. and Pai, Emil F. and Rottapel, Robert and Chirgadze, Nickolay Y.},
abstractNote = {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.},
doi = {10.1107/S1399004714017660},
journal = {Acta Crystallographica. Section D: Biological Crystallography (Online)},
number = 10,
volume = 70,
place = {United States},
year = {Thu Jul 31 00:00:00 EDT 2014},
month = {Thu Jul 31 00:00:00 EDT 2014}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 5works
Citation information provided by
Web of Science

Save / Share:
  • No abstract prepared.
  • Human microsomal cytochrome P-450 2E1 (CYP2E1) monooxygenates >70 low molecular weight xenobiotic compounds, as well as much larger endogenous fatty acid signaling molecules such as arachidonic acid. In the process, CYP2E1 can generate toxic or carcinogenic compounds, as occurs with acetaminophen overdose, nitrosamines in cigarette smoke, and reactive oxygen species from uncoupled catalysis. Thus, the diverse roles that CYP2E1 has in normal physiology, toxicity, and drug metabolism are related to its ability to metabolize diverse classes of ligands, but the structural basis for this was previously unknown. Structures of human CYP2E1 have been solved to 2.2 {angstrom} for an indazolemore » complex and 2.6 {angstrom} for a 4-methylpyrazole complex. Both inhibitors bind to the heme iron and hydrogen bond to Thr{sup 303} within the active site. Complementing its small molecular weight substrates, the hydrophobic CYP2E1 active site is the smallest yet observed for a human cytochrome P-450. The CYP2E1 active site also has two adjacent voids: one enclosed above the I helix and the other forming a channel to the protein surface. Minor repositioning of the Phe{sup 478} aromatic ring that separates the active site and access channel would allow the carboxylate of fatty acid substrates to interact with conserved {sup 216}QXXNN{sup 220} residues in the access channel while positioning the hydrocarbon terminus in the active site, consistent with experimentally observed {omega}-1 hydroxylation of saturated fatty acids. Thus, these structures provide insights into the ability of CYP2E1 to effectively bind and metabolize both small molecule substrates and fatty acids.« less
  • MAP kinase phosphatases (MKPs) have crucial roles in regulating the signaling activity of MAP kinases and are potential targets for drug discovery against human diseases. These enzymes contain a catalytic domain (CD) as well as a binding domain (BD) that help recognize the target MAP kinase. We report here the crystal structures at up to 2.2 {angstrom} resolution of the BD and CD of human MKP5 and compare them to the known structures from other MKPs. Dramatic structural differences are observed between the BD of MKP5 and that of MKP3 determined previously by NMR. In particular, the cluster of positivelymore » charged residues that is important for MAP kinase binding is located in completely different positions in the two structures, with a distance of 25 {angstrom} between them. Moreover, this cluster is {alpha}-helical in MKP5, while it forms a loop followed by a {beta}-strand in MKP3. These large structural differences could be associated with the distinct substrate preferences of these phosphatases, but further studies are needed to confirm this. The CD of MKP5 is observed in an active conformation, and two loops in the active site have backbone shifts of up to 5 {angstrom} relative to the inactive CDs from other MKPs.« less