Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.

ABSTRACT: Recently a novel inhibitor of Wnt signaling was discovered. The compound, WIKI4, was found to act through tankyrase inhibition and regulate ?-catenin levels in many cancer cell lines and human embryonic stem cells. Here we confirm that WIKI4 is a high potency tankyrase inhibitor and that it selectively inhibits tankyrases over other ARTD enzymes tested. The binding mode of the compound to tankyrase 2 was determined by protein X-ray crystallography to 2.4 Å resolution. The structure revealed a novel binding mode to the adenosine subsite of the donor NAD(+) binding groove of the catalytic domain. Our results form a structural basis for further development of potent and selective tankyrase inhibitors based on the WIKI4 scaffold.

SUBMITTER: Haikarainen T

PROVIDER: S-EPMC3675114 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.

Haikarainen Teemu T Venkannagari Harikanth H Narwal Mohit M Obaji Ezeogo E Lee Hao-Wei HW Nkizinkiko Yves Y Lehtiö Lari L

PloS one 20130606 6

Recently a novel inhibitor of Wnt signaling was discovered. The compound, WIKI4, was found to act through tankyrase inhibition and regulate β-catenin levels in many cancer cell lines and human embryonic stem cells. Here we confirm that WIKI4 is a high potency tankyrase inhibitor and that it selectively inhibits tankyrases over other ARTD enzymes tested. The binding mode of the compound to tankyrase 2 was determined by protein X-ray crystallography to 2.4 Å resolution. The structure revealed a no ...[more]

PMID: 23762361

Similar Datasets

WIKI4, a novel inhibitor of tankyrase and Wnt/ß-catenin signaling.

Project description:The Wnt/ß-catenin signaling pathway controls important cellular events during development and often contributes to disease when dysregulated. Using high throughput screening we have identified a new small molecule inhibitor of Wnt/ß-catenin signaling, WIKI4. WIKI4 inhibits expression of ß-catenin target genes and cellular responses to Wnt/ß-catenin signaling in cancer cell lines as well as in human embryonic stem cells. Furthermore, we demonstrate that WIKI4 mediates its effects on Wnt/ß-catenin signaling by inhibiting the enzymatic activity of TNKS2, a regulator of AXIN ubiquitylation and degradation. While TNKS has previously been shown to be the target of small molecule inhibitors of Wnt/ß-catenin signaling, WIKI4 is structurally distinct from previously identified TNKS inhibitors.

| S-EPMC3515623 | biostudies-literature

The structural basis of DKK-mediated inhibition of Wnt/LRP signaling.

Project description:Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) mediate canonical Wnt-?-catenin signaling by forming a complex with the co-receptor Frizzled, which binds to Wnt proteins. Dickkopf (DKK)-related proteins inhibit the Wnt signaling pathway by directly binding to the ectodomains of LRP5/6. However, the mechanism for DKK-mediated antagonism has not been fully understood as of yet. Crystal structures of the LRP6 ectodomain in complex with DKK1, along with mutagenesis studies, provide considerable insights into the molecular basis for DKK-mediated inhibition and Wnt signaling through LRP5/6.

| S-EPMC3465688 | biostudies-literature

Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6.

Project description:LDL receptor-related proteins 5 and 6 (LRP5/6) are coreceptors for Wnt growth factors, and also bind Dkk proteins, secreted inhibitors of Wnt signaling. The LRP5/6 ectodomain contains four ?-propeller/EGF-like domain repeats. The first two repeats, LRP6(1-2), bind to several Wnt variants, whereas LRP6(3-4) binds other Wnts. We present the crystal structure of the Dkk1 C-terminal domain bound to LRP6(3-4), and show that the Dkk1 N-terminal domain binds to LRP6(1-2), demonstrating that a single Dkk1 molecule can bind to both portions of the LRP6 ectodomain and thereby inhibit different Wnts. Small-angle X-ray scattering analysis of LRP6(1-4) bound to a noninhibitory antibody fragment or to full-length Dkk1 shows that in both cases the ectodomain adopts a curved conformation that places the first three repeats at a similar height relative to the membrane. Thus, Wnts bound to either portion of the LRP6 ectodomain likely bear a similar spatial relationship to Frizzled coreceptors.

| S-EPMC3215855 | biostudies-literature

Structural basis for tankyrase-RNF146 interaction reveals noncanonical tankyrase-binding motifs.

Project description:Poly(ADP-ribosyl)ation (PARylation) catalyzed by the tankyrase enzymes (Tankyrase-1 and -2; a.k.a. PARP-5a and -5b) is involved in mitosis, telomere length regulation, GLUT-4 vesicle transport, and cell growth and differentiation. Together with the E3 ubiquitin ligase RNF146 (a.k.a. Iduna), tankyrases regulate the cellular levels of several important proteins including Axin, 3BP2, and angiomotins, which are key regulators of Wnt, Src and Hippo signaling, respectively. These tankyrase substrates are first PARylated and then ubiquitylated by RNF146, which is allosterically activated by binding to PAR polymer. Each tankyrase substrate is recognized by a tankyrase-binding motif (TBM). Here we show that RNF146 binds directly to tankyrases via motifs in its C-terminal region. Four of these RNF146 motifs represent novel, extended TBMs, that have one or two additional amino acids between the most conserved Arg and Gly residues. The individual RNF146 motifs display weak binding, but together mediate a strong multivalent interaction with the substrate-binding region of TNKS, forming a robust one-to-one complex. A crystal structure of the first RNF146 noncanonical TBM in complex with the second ankyrin repeat domain of TNKS shows how an extended motif can be accommodated in a peptide-binding groove on tankyrases. Overall, our work demonstrates the existence of a new class of extended TBMs that exist in previously uncharacterized tankyrase-binding proteins including those of IF4A1 and NELFE.

| S-EPMC5980575 | biostudies-literature

The structural basis of Cryptosporidium -specific IMP dehydrogenase inhibitor selectivity.

Project description:Cryptosporidium parvum is a potential biowarfare agent, an important AIDS pathogen, and a major cause of diarrhea and malnutrition. No vaccines or effective drug treatment exist to combat Cryptosporidium infection. This parasite relies on inosine 5'-monophosphate dehydrogenase (IMPDH) to obtain guanine nucleotides, and inhibition of this enzyme blocks parasite proliferation. Here, we report the first crystal structures of CpIMPDH. These structures reveal the structural basis of inhibitor selectivity and suggest a strategy for further optimization. Using this information, we have synthesized low-nanomolar inhibitors that display 10(3) selectivity for the parasite enzyme over human IMPDH2.

| S-EPMC2819028 | biostudies-literature

Tankyrase is necessary for canonical Wnt signaling during kidney development.

Project description:Recent studies using small molecule antagonists have revealed that the poly(ADP-ribose) polymerases (PARPs) Tankyrase 1 and 2 are critical regulators of canonical Wnt signaling in some cellular contexts. However, the absence of any activity during zebrafish embryogenesis suggested that the tankyrases may not be general/core components of the Wnt pathway. Here, we show that Tnks1 and 2 are broadly expressed during mouse development and are essential during kidney and lung development. In the kidney, blockage of tankyrase activity phenocopies the effect of blocking production of all Wnt ligands. Tankyrase inhibition can be rescued by activation of beta-catenin demonstrating its specificity for the Wnt pathway. In addition, treatment with tankyrase inhibitors appears to be completely reversible in some cell types. These studies suggest that the tankyrases are core components of the canonical Wnt pathway and their inhibitors should enjoy broad usage as antagonists of Wnt signaling.

| S-EPMC2925040 | biostudies-literature

Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells.

Project description:Maintenance of chromosomal ends (telomeres) directly contributes to cancer cell immortalization. The telomere protection enzymes belonging to the tankyrase (Tnks) subfamily of poly(ADP-ribose) polymerases (PARPs) have recently been shown to also control transcriptional response to secreted Wnt signaling molecules. Whereas Tnks inhibitors are currently being developed as therapeutic agents for targeting Wnt-related cancers and as modulators of Wnt signaling in tissue-engineering agendas, their impact on telomere length maintenance remains unclear. Here, we leveraged a collection of Wnt pathway inhibitors with previously unassigned mechanisms of action to identify novel pharmacophores supporting Tnks inhibition. A multifaceted experimental approach that included structural, biochemical, and cell biological analyses revealed two distinct chemotypes with selectivity for Tnks enzymes. Using these reagents, we revealed that Tnks inhibition rapidly induces DNA damage at telomeres and telomeric shortening upon long-term chemical exposure in cultured cells. On the other hand, inhibitors of the Wnt acyltransferase Porcupine (Porcn) elicited neither effect. Thus, Tnks inhibitors impact telomere length maintenance independently of their affects on Wnt/β-catenin signaling. We discuss the implications of these findings for anticancer and regenerative medicine agendas dependent upon chemical inhibitors of Wnt/β-catenin signaling.

| S-EPMC4475917 | biostudies-literature

Ubiquitin ligase RNF146 regulates tankyrase and Axin to promote Wnt signaling.

Project description:Canonical Wnt signaling is controlled intracellularly by the level of ?-catenin protein, which is dependent on Axin scaffolding of a complex that phosphorylates ?-catenin to target it for ubiquitylation and proteasomal degradation. This function of Axin is counteracted through relocalization of Axin protein to the Wnt receptor complex to allow for ligand-activated Wnt signaling. AXIN1 and AXIN2 protein levels are regulated by tankyrase-mediated poly(ADP-ribosyl)ation (PARsylation), which destabilizes Axin and promotes signaling. Mechanistically, how tankyrase limits Axin protein accumulation, and how tankyrase levels and activity are regulated for this function, are currently under investigation. By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. RNF146 also destabilizes tankyrases TNKS1 and TNKS2 proteins and, in a reciprocal relationship, tankyrase activity reduces RNF146 protein levels. We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation. RNF146 is a cytoplasmic protein that also prevents tankyrase protein aggregation at a centrosomal location. Tankyrase auto-PARsylation and PARsylation of Axin is known to lead to proteasome-mediated degradation of these proteins, and we demonstrate that, through ubiquitylation, RNF146 mediates this process to regulate Wnt signaling.

| S-EPMC3143158 | biostudies-literature

Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase.

Project description:Indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are two of the only three heme-based dioxygenases in humans. They have recently been identified as key cancer immunotherapeutic drug targets. While structures of hIDO1 in complex with inhibitors have been documented, so far there are no structures of hTDO-inhibitor complexes available. Here we use PF-06840003 (IPD), a hIDO1-selective inhibitor in clinical trials, as a structural probe to elucidate inhibitor-selectivity in hIDO1 versus hTDO. Spectroscopic studies show that IPD exhibits 400-fold higher inhibition activity toward hIDO1 with respect to hTDO. Crystallographic structures reveal that the binding pocket of IPD in the active site in hIDO1 is much more flexible as compared to that in hTDO, which offers a molecular explanation for the superior inhibition activity of IPD in hIDO1 with respect to hTDO. In addition to the IPD bound in the active site, a second IPD molecule was identified in an inhibitory site on the proximal side of the heme in hIDO1 and in an exosite that is ?40 Å away from the active site in hTDO. Taken together the data provide new insights into structure-based design of mono and dual inhibitors targeting hIDO1 and/or hTDO.

| S-EPMC7366343 | biostudies-literature

mTOR signaling mediates resistance to tankyrase inhibitors in Wnt-driven colorectal cancer.

Project description:Activation of Wnt/?-catenin signaling is essential for colorectal carcinogenesis. Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, is a positive regulator of the Wnt/?-catenin signaling. Accordingly, tankyrase inhibitors are under preclinical development for colorectal cancer (CRC) therapy. However, Wnt-driven colorectal cancer cells are not equally sensitive to tankyrase inhibitors, and cellular factors that affect tankyrase inhibitor sensitivity remain elusive. Here, we established a tankyrase inhibitor-resistant cell line, 320-IWR, from Wnt/?-catenin-dependent CRC COLO-320DM cells. 320-IWR cells exhibited resistance to tankyrase inhibitors, IWR-1 and G007-LK, but remained sensitive to a PARP-1/2 inhibitor, olaparib, and several anti-CRC agents. In 320-IWR cells, nuclear localization of active ?-catenin was decreased and expression of ?-catenin target genes was constitutively repressed, suggesting that these cells repressed the Wnt/?-catenin signaling and were dependent on alternative proliferation pathways. 320-IWR cells exhibited upregulated mTOR signaling and were more sensitive to mTOR inhibition than the parental cells. Importantly, mTOR inhibition reversed resistance to tankyrase inhibitors and potentiated their anti-proliferative effects in 320-IWR cells as well as in CRC cell lines in which the mTOR pathway was intrinsically activated. These results indicate that mTOR signaling confers resistance to tankyrase inhibitors in CRC cells and suggest that the combination of tankyrase and mTOR inhibitors would be a useful therapeutic approach for a subset of CRCs.

| S-EPMC5564614 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data