Hildmann, Christian

[["dc.bibliographiccitation.firstpage","270"],["dc.bibliographiccitation.journal","Acta Crystallographica Section F Structural Biology and Crystallization Communications"],["dc.bibliographiccitation.lastpage","273"],["dc.bibliographiccitation.volume","63"],["dc.contributor.author","Nielsen, Tine Kragh"],["dc.contributor.author","Hildmann, Christian"],["dc.contributor.author","Riester, Daniel"],["dc.contributor.author","Wegener, Dennis"],["dc.contributor.author","Schwienhorst, Andreas"],["dc.contributor.author","Ficner, Ralf"],["dc.date.accessioned","2017-09-07T11:49:48Z"],["dc.date.available","2017-09-07T11:49:48Z"],["dc.date.issued","2007"],["dc.description.abstract","Histone deacetylases (HDACs) have emerged as attractive targets in anticancer drug development. To date, a number of HDAC inhibitors have been developed and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA). Not surprisingly, structural information that can greatly enhance the design of novel HDAC inhibitors is so far only available for hydroxamic acids in complex with HDAC or HDAC-like enzymes. Here, the first structure of an enzyme complex with a nonhydroxamate HDAC inhibitor is presented. The structure of the trifluoromethyl ketone inhibitor 9,9,9-trifluoro-8-oxo-N-phenylnonanamide in complex with bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) has been determined. HDAH reveals high sequential and functional homology to human class 2 HDACs and a high structural homology to human class 1 HDACs. Comparison with the structure of HDAH in complex with SAHA reveals that the two inhibitors superimpose well. However, significant differences in binding to the active site of HDAH were observed. In the presented structure the O atom of the trifluoromethyl ketone moiety is within binding distance of the Zn atom of the enzyme and the F atoms participate in interactions with the enzyme, thereby involving more amino acids in enzyme-inhibitor binding."],["dc.identifier.doi","10.1107/S1744309107012377"],["dc.identifier.gro","3143512"],["dc.identifier.isi","000245505800004"],["dc.identifier.pmid","17401192"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1034"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Blackwell Publishing"],["dc.relation.issn","1744-3091"],["dc.title","Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","258"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.lastpage","270"],["dc.bibliographiccitation.volume","124"],["dc.contributor.author","Hildmann, Christian"],["dc.contributor.author","Wegener, Dennis"],["dc.contributor.author","Riester, Daniel"],["dc.contributor.author","Hempel, Rene"],["dc.contributor.author","Schober, Andreas"],["dc.contributor.author","Merana, Joachim"],["dc.contributor.author","Giurato, Laura"],["dc.contributor.author","Guccione, Salvatore"],["dc.contributor.author","Nielsen, Tine Kragh"],["dc.contributor.author","Ficner, Ralf"],["dc.contributor.author","Schwienhorst, Andreas"],["dc.date.accessioned","2017-09-07T11:52:42Z"],["dc.date.available","2017-09-07T11:52:42Z"],["dc.date.issued","2006"],["dc.description.abstract","Histone deacetylases (HDACs) are key enzymes in the transcriptional regulation of gene expression in eukaryotic cells. In recent years MACs have attracted considerable attention as promising new targets in anticancer therapy. Currently, different histone deacetylase subtypes are divided into four groups denoted as classes 1-4. Here, we compare in more detail representatives of class I HDACs and FB188 HDAH as a close bacterial homologue of class 2 HDAC6, in regard of substrate and inhibitor specificity. Structure comparison is used to identify candidate regions responsible for observed specificity differences. Knowledge of these structural elements expedite studies on the biochemical role of different HDAC subtypes as well as the development of highly selective HDAC inhibitors as antitumor agents. (c) 2006 Elsevier B.V. All rights reserved."],["dc.identifier.doi","10.1016/j.jbiotec.2006.01.030"],["dc.identifier.gro","3143672"],["dc.identifier.isi","000238620900022"],["dc.identifier.pmid","16567013"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1211"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Elsevier Science Bv"],["dc.publisher.place","Amsterdam"],["dc.relation.eissn","1873-4863"],["dc.relation.eventlocation","Wiesbaden, GERMANY"],["dc.relation.ispartof","Journal of Biotechnology"],["dc.relation.issn","0168-1656"],["dc.title","Substrate and inhibitor specificity of class 1 and class 2 histone deacetylases"],["dc.type","conference_paper"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","107"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Journal of Molecular Biology"],["dc.bibliographiccitation.lastpage","120"],["dc.bibliographiccitation.volume","354"],["dc.contributor.author","Nielsen, Tine Kragh"],["dc.contributor.author","Hildmann, Christian"],["dc.contributor.author","Dickmanns, Achim"],["dc.contributor.author","Schwienhorst, Andreas"],["dc.contributor.author","Ficner, Ralf"],["dc.date.accessioned","2017-09-07T11:53:41Z"],["dc.date.available","2017-09-07T11:53:41Z"],["dc.date.issued","2005"],["dc.description.abstract","Histone deacetylases (HDACs) are among the most promising targets in cancer therapy. However, structural information greatly enhancing the design of HDAC inhibitors as novel chemotherapeutics has not been available on class 2 HDACs so far. Here we present the structure of the bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) that reveals high sequential and functional homology to human class 2 HDACs. FB188 HDAH is capable to remove the acetyl moiety from acetylated histones. Several HDAC specific inhibitors, which have been shown to inhibit tumor activity in both pre-clinical models and in clinical trials, also inhibit FB188 HDAH. We have determined the crystal structure of FB188 HDAH at a resolution of 1.6 angstrom in complex with the reaction product acetate, as well as in complex with the inhibitors suberoylanilide hydroxamic acid (SAHA) and cyclopentyle-propionyle hydroxamic acid (CypX) at a resolution of 1.57 angstrom and 1.75 angstrom, respectively. FB188 HDAH exhibits the canonical fold of class 1 HDACs and contains a catalytic zinc ion. The highest structural diversity compared to class 1 enzymes is found in loop regions especially in the area around the entrance of the active site, indicating significant differences among the acetylated proteins binding to class I and 2 HDACs, respectively. (c) 2005 Elsevier Ltd. All rights reserved."],["dc.identifier.doi","10.1016/j.jmb.2005.09.065"],["dc.identifier.gro","3143786"],["dc.identifier.isi","000233310800008"],["dc.identifier.pmid","16242151"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1338"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0022-2836"],["dc.title","Crystal Structure of a Bacterial Class 2 Histone Deacetylase Homologue"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]