Crystal Structure of the Catalytic Domain of Human PARP2 in Complex with PARP Inhibitor ABT-888

Karlberg, T.; Hammarstrom, M.; Schutz, P.; Svensson, L.; Schüler, H.

doi:10.1021/bi902079y

Cited by 75 publications

(72 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Unfortunately the precise inhibitory mechanism could not be evaluated by this kit. Accordingly, to gain further insight, we constructed an initial structural model of the PARP-1-AThTP complex by considering the X-ray structures of the PARP-1-ADP analogue complex ( 15 ) and the PARP2-PARP inhibitor (ABT-888) complex ( 16 ), deposited in the Protein Data Bank (http://www.rcsb.org./pdb/) as 1A26 and 3KJD. The energy-minimized structure after 200 ps of molecular dynamics simulations is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The poly (ADP-ribose) chain (acceptor) and an NAD ϩ molecule (donor) would bind to PARP-1 via the ADP and ABT-888 binding sites, respectively. The NAD ϩ nicotinamide moiety is thought to be stabilized by the ABT-888 binding site, especially Tyr907 via ring-stacking interactions ( 16 ), and many PARP-1 inhibitors have been created mainly for binding to this ''donor'' binding site. By comparing these binding modes, it appears that AThTP in the structure of the PARP-1 complex could interact with both binding sites at the same time.…”

Section: Resultsmentioning

confidence: 99%

“…Adenosine and the triphosphate of AThTP were modeled from this ADP molecule. The PARP-1 binding structure of the AThTP thiamin moiety was constructed by referring to the ABT-888 binding to PARP2 (PDB code: 3KJD) ( 16 ). The thiazole and pyrimidine rings of the thiamin moiety were positioned in a similar location to the imidazole and pyrrolidine rings of ABT-888.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Adenosine Thiamine Triphosphate (AThTP) Inhibits Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activity

Tanaka

Yamamoto

Sato

et al. 2011

J Nutr Sci Vitaminol

View full text Add to dashboard Cite

Summary Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) has been demonstrated to result in various stress-related diseases, including diabetes mellitus. Deficiency of cellular nicotinamide adenine dinucleotide (NAD ϩ ) content, consumed by PARP-1 to add ADP-ribose moieties onto target proteins, contributes to pathophysiological conditions. Adenosine thiamine triphosphate (AThTP) exists in small amounts in mammals; however, the function(s) of this metabolite remains unresolved. The structure of AThTP resembles NAD Substantial recent experimental studies demonstrate beneficial impacts of high-dose thiamine on diabetic complications, such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy and diabetic cardiomyopathy ( 1-4 ). However, the pharmacological relevance of high-dose thiamine treatments remains unknown.Chronic hyperglycemia results in diabetic complications in target organs. The pathogenic effect of high glucose is, at least partially, mediated to a significant extent through increased production of reactive oxygen species and reactive nitrogen species and subsequent oxidative stress (reviewed in Evans et al. ( 5 )). Increased oxidative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 activation depletes its substrate, nicotinamide adenine dinucleotide (NAD ϩ ), and also covalently attaches branched nucleic acid-like polymers of poly(ADP-ribose) to various acceptor proteins (reviewed in Kiss and Szabó ( 6 )). A covalently attached ADP-ribose polymer, poly(ADP-ribosylation, affects the function of target proteins. The involvement of PARP-1 activation in the pathogenesis of diabetes and its complications has recently been emphasized by both in vivo and in vitro studies (reviewed in Pacher and Szabó ( 7 ), and Szabó ( 8 )). NAD ϩ , used as substrate for PARP-1, consists of two nucleotides joined through their phosphate groups, with one nucleotide containing an adenine base and the other containing nicotinamide.Adenosine thiamine triphosphate (AThTP), a new thiamine derivative, was recently identified in Escherichia coli ( 9 ), followed by the identification in small amounts in mouse brain, heart, skeletal muscle, liver and kidneys ( 10 ). AThTP is composed of two molecules, an adenine base and thiamine, which are joined through phosphate groups. The structure of AThTP appears to closely resemble NAD ϩ . Although the biological role of AThTP is unknown, the existence of noncoenzyme functions of thiamine derivatives has been speculated (11)(12)(13)(14).In the context of 1) structural resemblance of AThTP to NAD ϩ , 2) the experimental evidence implicating PARP-1 as a causative factor in the pathogenesis of diabetes and diabetic complications in vitro and in vivo (reviewed in Szabó ( 8 )), and 3) beneficial effects of highdose thiamine on diabetic complications, we hypothesized that AThTP could interact with PARP-1 and mod-E-mail: t.tanaka.md@gmail.com Abbreviations: AThTP, adenosine thiamine triphosphate; NAD ϩ , nicotinamide adenine dinucleotide; PARP...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Adenosine Thiamine Triphosphate (AThTP) Inhibits Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activity

Tanaka

Yamamoto

Sato

et al. 2011

J Nutr Sci Vitaminol

View full text Add to dashboard Cite

show abstract

“…Domain F is separated from domain E by a caspase-8 cleavage site [29]. PARP-2 and PARP-1 share a catalytic domain of 69% similarity, with the exception that PARP-2 contains an additional three amino acid insertion in the loop connecting the β-strands k and l in PARP-1 [8,30,31] (Fig. 3.).…”

Section: The Parp Superfamilymentioning

confidence: 99%

“…However, all known PARP inhibitors are capable of inhibiting both PARP-1 and -2, which is not surprising since the catalytic domain of the enzymes are very similar and most PARP inhibitors bind there [30,31]. In the quest for synthesizing PARP-2 specific inhibitors, the laboratory of Gilbert de Murcia suggested the targeting of a loop that is unique in PARP-2, [25,30].…”

Section: Parp-2 In Oxidative Stress-related Diseasesmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Abstract:Poly(ADP-ribose) polymerase (PARP)-2 is a nuclear enzyme that belongs to the PARP family and PARP-2 is responsible for 5-15% of total cellular PARP activity. PARP-2 was originally described in connection to DNA repair and in physiological and pathophysiological processes associated with genome maintenance (e.g. centromere and telomere protection, spermiogenesis, thymopoesis, azoospermia and tumorigenesis). Recent reports identified important rearrangements in gene expression upon the knockout of PARP-2. Such rearrangements heavily impact on inflammation and metabolism. Metabolic effects are mediated through modifying PPARg and SIRT1 function. Altered gene expression gives rise to a complex phenotype characterized primarily by enhanced mitochondrial activity that results both in beneficial (loss of fat, enhanced insulin sensitivity) and in disadvantageous (pancreatic beta cell hypofunction upon high fat feeding) consequences. Enhanced mitochondrial biogenesis provides protection in oxidative stress related diseases. Hereby, we review the recent developments in PARP-2 research with special attention to the involvement of PARP-2 in transcriptional and metabolic regulation. We would like to thank the referee for his/her efforts to further improve our manuscript.1. Page 2 -the modifications here are fairly minimalistic and the abbreviations ARTD2 and ARTD1 are not even defined. Powered by Editorial Manager® and Preprint Manager® from Aries Systems Corporationand ARTD1 are not even defined.In the corresponding section we incorporated the basic information on the newly proposed nomenclature in our previous version upon the suggestion of the Reviewer. We agree with the Reviewer that the appearance of the new nomenclature in our manuscript is important. Moreover, in the current version we added ARTD-2 as a keyword to help those future readers that follow the new nomenclature. The fact that ARTD1 is the equivalent of PARP-1 is defined in the chapter "PARP superfamily" second paragraph, first row. We added the abbreviation of ARDT-2 in the last sentence in the first paragraph of the chapter "The PARP superfamily". We think that these are sufficient for the understanding of the position of PARP-2 in the PARP/ARTD superfamily.We would like to note here, that the proposed new nomenclature did not gain ground in the scientific community yet. There are only 3 relevant papers on Medline for the keyword ARTD1, ARTD2 or ARTD (since 2010, the publication of the paper by In summary, we are confident that our review sufficiently takes the new nomenclature into consideration despite of the fact that it is not yet accepted by the scientific community. Sequence homology modeling was carried out by Ame and co-workers (Ame et al. Bioessays. 26:882-893. 2004). They classified sequences as PARPs on the basis of sequence homology, therefore sequence homology does exist. However, mutation(s) in a sequence does not necessarily mean that sequence homology is lost. In the incriminated text, mutations mean rather point mutations that aff...

show abstract

Medicinal Chemistry in the Context of the Human Genome

Brunschweiger

Hall

2013

Methods and Principles in Medicinal Chemistry

View full text Add to dashboard Cite

Crystal Structure of the Catalytic Domain of Human PARP2 in Complex with PARP Inhibitor ABT-888

Cited by 75 publications

References 20 publications

Adenosine Thiamine Triphosphate (AThTP) Inhibits Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activity

Adenosine Thiamine Triphosphate (AThTP) Inhibits Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activity

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Medicinal Chemistry in the Context of the Human Genome

Contact Info

Product

Resources

About