Research Area E - Publications 2015

J. Cell Biol., Vol. 212, No. 1, 63–75,
J. Cell Biol., online article



Cellular genomes are highly vulnerable to perturbations to chromosomal DNA replication. Proliferating cell nuclear antigen (PCNA), the processivity factor for DNA replication, plays a central role as a platform for recruitment of genome surveillance and DNA repair factors to replication forks, allowing cells to mitigate the threats to genome stability posed by ...



CIPSM wishing you and your family a wonderful holiday season and a healthy & peaceful New Year 2016!



J. Proteome Res., 15 (3), pp 755–765, DOI: 10.1021/acs.jproteome.5b00824
J. Proteome Res., online article


Increasingly, multiple omics approaches are being applied to understand the complexity of biological systems. Yet, computational approaches that enable the efficient integration of such data are not well developed. Here, we describe a novel algorithm, termed moCluster, which discovers joint patterns among multiple omics data. The method first employs a multiblock ...


Angew. Chem. Int. Ed. 2015, 54, 15565 –15569, DOI: 10.1002/anie.201506384
Angew. Chem. Int. Ed., online article


Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off‐target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic ...


Angew. Chem. Int. Ed., Volume 55, Issue 3, Pages 858–860, DOI: 10.1002/anie.201510402
Angew. Chem. Int. Ed., online article


Enoyl-CoA carboxylase/reductases (ECRs) catalyze the selective α-carboxylation of α,β-unsaturated CoA-thioesters. Structure-based engineering of the active-site binding pocket of ECRs enabled significant alteration of their catalytic activity towards larger substrates. This facilitates the incorporation of unusual extender units into polyketide backbones, thus ...


J. Am. Chem. Soc., DOI: 10.1021/jacs.5b09753

J. Am. Chem. Soc., online article


Absorption of UV-radiation in nucleotides initiates a number of photophysical and photochemical processes, which may finally cause DNA damage. One major decay channel of photoexcited DNA leads to reactive charge transfer states. This study shows that these states trigger self-repair of DNA photolesions. The experiments were performed by UV spectroscopy and HPLC ...


Angew. Chem. Int. Ed., Volume 55, Issue 3, Pages 1187–1191, DOI: 10.1002/anie.201508052

Angew. Chem. Int. Ed., online article


Vibrio is a model organism for the study of quorum sensing (QS) signaling and is used to identify QS-interfering drugs. Naturally occurring fimbrolides are important tool compounds known to affect QS in various organisms; however, their cellular targets have so far remained elusive. Here we identify the irreversible fimbrolide targets in the proteome of living V. ...


ACS Chem. Biol., DOI: 10.1021/acschembio.5b00757

ACS Chem. Biol., online article



ClpP is a self-compartmentalizing protease with crucial roles in bacterial and mitochondrial protein quality control. Although the ClpP homocomplex is composed of 14 equivalent active sites, it degrades a multitude of substrates to small peptides, demonstrating its capability to carry out diverse cleavage reactions. Here, we show that ClpP proteases from E. coli, ...



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Angew. Chem. Int. Ed., Volume 54, Issue 52, Pages 15892–15896 , DOI: 10.1002/anie.201507266

Angew. Chem. Int. Ed., online article


Caseinolytic protease P (ClpP) is an important regulator of Staphylococcus aureus pathogenesis. A high-throughput screening for inhibitors of ClpP peptidase activity led to the identification of the first non-covalent binder for this enzyme class. Co-crystallization of the small molecule with S. aureus ClpP revealed a novel binding mode: Because of the rotation ...


Angew. Chem. 2015, 127, 1 – 6, DOI: 10.1002/ange.201506384

Angew. Chem., online article


Inkretin-Mimetika sind auf dem besten Weg, sich zu einer tragenden Säule in der Typ-2-Diabetes-Behandlung zu entwickeln. Durch ihre Wirkung auf die Bauchspeicheldrüse und das Gehirn verstärken sie die Insulinsekretion, induzieren einen Gewichtsverlust und halten die Normoglykämie aufrecht. Allerdings wird die Inkretin-Therapie mit Nebenwirkungen wie Übelkeit und ...


Endocrinology, 157(1):233–244, doi: 10.1210/en.2015-1519
Endocrinology, online article


Body weight loss of Lepob/ob mice in response to leptin is larger than expected from the reduction in energy intake alone, suggesting a thermogenic action of unknown magnitude. We exploited the superior pharmacological properties of a novel long-acting leptin prepared via PASylation to study the contribution of its anorexigenic and thermogenic effects. ...


Food Microbiology, Volume 46, Pages 553–563, doi:10.1016/

Food Microbiology, online article


The main bittering component in beer, hop iso-α-acids, have been characterised as weak acids, which act as ionophores impairing microbial cells' function under acidic conditions as present in beer. Besides medium pH, divalent cations play a central role regarding the efficacy of the antimicrobial effect. The iso-α-acids' non-bitter derivatives humulinic acids can ...


International Journal of Cancer, Volume 138, Issue 5, Pages 1269–1280, DOI: 10.1002/ijc.29874
International Journal of Cancer, online article


The standard of care for diagnosis and therapy monitoring of gliomas is magnetic resonance imaging (MRI), which however, provides only an indirect and incomplete representation of the tumor mass, offers limited information for patient stratification according to WHO-grades and may insufficiently indicate tumor relapse after antiangiogenic therapy. Anticalins are ...


Nature Communications, 6, Article number: 8406, doi:10.1038/ncomms9406

Nature Communications, online article


Photodriven molecular motors are able to convert light energy into directional motion and hold great promise as miniaturized powering units for future nanomachines. In the current state of the art, considerable efforts have still to be made to increase the efficiency of energy transduction and devise systems that allow operation in ambient and non-damaging ...


Protein Engineering, Design and Selection, vol. 28 no. 12, pp. 553–565, doi: 10.1093/protein/gzv048

Protein Engineering, Design and Selection, online article


The bioorthogonal keto group has attracted interest for the site-specific chemical conjugation of recombinant proteins under mild conditions, e.g. with aminooxy-functionalised fluorescent probes, radiometal chelates, toxins or polymers. However, the cotranslational incorporation of the corresponding non-canonical amino acid p-acetyl-l-phenylalanine (Apa) into ...


ACS Chem. Biol., 10 (12), pp 2743–2752, DOI: 10.1021/acschembio.5b00616

ACS Chem. Biol., online article


Protein kinases are important mediators of intracellular signaling and are reversibly activated by phosphorylation. Immobilized kinase inhibitors can be used to enrich these often low-abundance proteins, to identify targets of kinase inhibitors, or to probe their selectivity. It has been suggested that the binding of kinases to affinity beads reflects a kinase’s ...


Angew. Chem. Int. Ed., Volume 54, Issue 46, Pages 13550–13554, DOI: 10.1002/anie.201505749

Angew. Chem. Int. Ed., online article


Analogues of the natural product duocarmycin bearing an indole moiety were shown to bind aldehyde dehydrogenase 1A1 (ALDH1A1) in addition to DNA, while derivatives without the indole solely addressed the ALDH1A1 protein. The molecular mechanism of selective ALDH1A1 inhibition by duocarmycin analogues was unraveled through cocrystallization, mutational studies, ...


Angew. Chem. Int. Ed., Volume 54, Issue 46, Pages 13508–13514, DOI: 10.1002/anie.201504741

Angew. Chem. Int. Ed., online article


The field of biology has been revolutionized by the recent advancement of an adaptive bacterial immune system as a universal genome engineering tool. Bacteria and archaea use repetitive genomic elements termed clustered regularly interspaced short palindromic repeats (CRISPR) in combination with an RNA-guided nuclease (CRISPR-associated nuclease: Cas) to target ...


Biotechnology and Applied Biochemistry, Volume 63, Issue 5, Pages 616–624, DOI: 10.1002/bab.1414
Biotechnology and Applied Biochemistry, online article


The l-alanine dehydrogenase of Bacillus subtilis (BasAlaDH), which is strictly dependent on NADH as redox cofactor, efficiently catalyzes the reductive amination of pyruvate to l-alanine using ammonia as amino group donor. To enable application of BasAlaDH as regenerating enzyme in coupled reactions with NADPH-dependent alcohol dehydrogenases, we alterated its ...


Chem. Commun., 51, 15784-15787, DOI: 10.1039/C5CC06424D

Chem. Commun., online article


Falcarinol and stipudiol are natural products with potent anti-cancer activity found in several vegetables. Here, we use a chemical proteomic strategy to identify ALDH2 as a molecular target of falcarinol in cancer cells and confirm enzyme inhibition via covalent alkylation of the active site. Furthermore, the synthesis of stipudiol led to the observation that ...


Appl Microbiol Biotechnol, Volume 99, Issue 24, pp 10501-10513, DOI 10.1007/s00253-015-6930-5

Appl Microbiol Biotechnol, online article


The thermostable NAD+-dependent alcohol dehydrogenase from Geobacillus stearothermophilus (BsADH) was exploited with regard to the biocatalytic synthesis of ω-oxo lauric acid methyl ester (OLAMe), a key intermediate for biobased polyamide 12 production, from the corresponding long-chain alcohol. Recombinant BsADH was produced in Escherichia coli as a homogeneous ...


ChemPlusChem, Volume 80, Issue 11, pages 1673–1679, DOI: 10.1002/cplu.201500246

ChemPlusChem, online article


Natural products comprise a rich source for bioactive molecules with medicinal relevance. Many of these contain electrophilic scaffolds that bind conserved enzyme active sites covalently. Prominent examples include beta-lactams and beta-lactones, which specifically acylate serine residues in diverse peptidases. Although these scaffolds appear similar, their ...


Tetrahedron Letters, 56, 4266–4274, doi:10.1016/j.tetlet.2015.05.022

Tetrahedron Letters, online article


Hemithioindigo (HTI) is an emerging photoswitch with many advantageous properties compared to the commonly used photoswitches like azobenzenes, spiropyranes, or dithienylethenes. In this DIGEST the syntheses, physical and photophysical properties of HTI photoswitches and mechanistic explanations for the latter are reviewed. Emphasis will be placed on those ...


PNAS, vol. 112 no. 27, 8272–8277, doi: 10.1073/pnas.1508509112

PNAS, online article


Nucleotide excision repair (NER) is responsible for the removal of a large variety of structurally diverse DNA lesions. Mutations of the involved proteins cause the xeroderma pigmentosum (XP) cancer predisposition syndrome. Although the general mechanism of the NER process is well studied, the function of the XPA protein, which is of central importance for ...


Angewandte Chemie International Edition 54, 1 – 5, DOI: 10.1002/anie.201502722

Angewandte Chemie International Edition, online article


The absolute levels of 5-hydroxymethylcytosine (hmC) and 5-methylcytosine (mC) in human brain tissues at various ages were determined. Additionally, absolute levels of 5-formylcytosine (fC) in adult individuals and cytosine modification levels in sorted neurons were quantified. These data were compared with age-related fC, hmC, and mC levels in mouse brain ...


Cell Reports, Volume 12, Issue 2, p183–189,

Cell Reports, online article


Alternative splicing acts on transcripts from almost all human multi-exon genes. Notwithstanding its ubiquity, fundamental ramifications of splicing on protein expression remain unresolved. The number and identity of spliced transcripts that form stably folded proteins remain the sources of considerable debate, due largely to low coverage of experimental methods ...


J. Phys. Chem. B, 2015, DOI: 10.1021/acs.jpcb.5b04694, 119 (28), pp 8685–8692 published on 23.06.2015
J. Phys. Chem. B, online article


UV-induced Dewar lesion formation is investigated in single- and double-stranded oligonucleotides with ultrafast vibrational spectroscopy. The quantum yield for the conversion of the (6–4) lesion to the Dewar isomer in DNA strands is reduced by a factor of 4 in comparison to model dinucleotides. Time resolved spectroscopy reveals a fast process in the excited ...


JACS, 2015, DOI: 10.1021/jacs.5b03084, 137 (26), pp 8475–8483 published on 17.06.2015
JACS, online article

Caseinolytic protease P (ClpP) represents a central bacterial degradation machinery that is involved in cell homeostasis and pathogenicity. The functional role of ClpP has been studied by genetic knockouts and through the use of beta-lactones, which remain the only specific inhibitors of ClpP discovered to date. Beta-lactones have served as chemical tools to ...


Proteomics, Volume 15, Issue 17, Pages 3066–3074, DOI 10.1002/pmic.201400324

Proteomics, online article


The Janus Kinase (JAK) signaling pathway plays a key role for many cellular processes and has recently been correlated with neuronal disorders. In order to understand new links of JAK family members with other signaling pathways, chemical proteomics tools with broad kinase coverage are desirable. A probe that shows outstanding kinase selectivity and allows for ...


Molecular Cell, 2015, doi:10.1016/j.molcel.2015.05.009, 59, 1–14, published on 04.06.2015
Molecular Cell, online article


Histone variants are emerging as key regulatory molecules in cancer. We report a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the ...


 J Nucl Med., 56, no. 7 , 1112–1118, DOI: 10.2967/jnumed.114.149690

 J Nucl Med., online article


Immuno-PET imaging of the tumor antigen HER2/neu allows for the noninvasive detection and monitoring of oncogene expression; such detection and monitoring are of prognostic value in patients with breast cancer. Compared with the full-size antibody trastuzumab, smaller protein tracers with more rapid blood clearance permit higher imaging contrast at earlier time ...


Molecular & Cellular Proteomics, 14, 2394-2404, doi: 10.1074/mcp.M114.046995

Molecular & Cellular Proteomics, online article


Calculating the number of confidently identified proteins and estimating false discovery rate (FDR) is a challenge when analyzing very large proteomic data sets such as entire human proteomes. Biological and technical heterogeneity in proteomic experiments further add to the challenge and there are strong differences in opinion regarding the conceptual validity ...


J. Proteome Res., 14 (6), pp 2617–2625, DOI: 10.1021/acs.jproteome.5b00161

J. Proteome Res., online article


Tyrosine kinase inhibitors (TKIs) have become an important therapeutic option for treating several forms of cancer. Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR), is in clinical use for treating non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. However, despite high initial response rates, many patients develop ...


Cell, Volume 161, Issue 4, p919–932,

Cell, online article


Aging has been associated with a progressive decline of proteostasis, but how this process affects proteome composition remains largely unexplored. Here, we profiled more than 5,000 proteins along the lifespan of the nematode C. elegans. We find that one-third of proteins change in abundance at least 2-fold during aging, resulting in a severe proteome imbalance. ...


Science, 2015, DOI: 10.1126/science.1253671, Vol. 348 no. 6234 published on 01.05.2015
Science, online article

DNA interstrand cross-links (ICLs) block replication fork progression by inhibiting DNA strand separation. Repair of ICLs requires sequential incisions, translesion DNA synthesis, and homologous recombination, but the full set of factors involved in these transactions remains unknown. We devised a technique called chromatin mass spectrometry (CHROMASS) to study ...


Cell Reports, 2015,, 11, 1–12 published on 14.04.2015
Cell Reports, online article

Ten-eleven translocation hydroxylases (TET1-3) oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). In neurons, increased 5hmC levels within gene bodies correlate positively with gene expression. The mechanisms controlling TET activity and 5hmC levels are poorly understood. In particular, it is not known how the neuronal TET3 isoform lacking a ...


Proteins, Volume 83, Issue 6, Pages 1180–1184, DOI: 10.1002/prot.24797

Proteins, online article


Human odorant-binding protein, OBPIIa, is expressed by nasal epithelia to facilitate transport of hydrophobic odorant molecules across the aqueous mucus. Here, we report its crystallographic analysis at 2.6 Å resolution. OBPIIa is a monomeric protein that exhibits the classical lipocalin fold with a conserved eight-stranded β-barrel harboring a remarkably large ...


Chemistry - A European Journal, Volume 21, Issue 21, pages 7701–7704, DOI: 10.1002/chem.201500971

Chemistry - A European Journal, online article


We here report the construction of an E. coli expression system able to manufacture an unnatural amino acid by artificial biosynthesis. This can be orchestrated with incorporation into protein by amber stop codon suppression inside a living cell. In our case an alkyne-bearing pyrrolysine amino acid was biosynthesized and incorporated site-specifically allowing ...


Mol. Pharmaceutics, 12 (5), pp 1431–1442, DOI: 10.1021/mp5007147

Mol. Pharmaceutics, online article



Leptin plays a central role in the control of energy homeostasis and appetite and, thus, has attracted attention for therapeutic approaches in spite of its limited pharmacological activity owing to the very short circulation in the body. To improve drug delivery and prolong plasma half-life, we have fused murine leptin with Pro/Ala/Ser (PAS) polypeptides of up to ...


Chemistry & Biology, 2015, DOI:, Volume 22, Issue 3, p404–411, published on 19.03.2015
Chemistry & Biology, online article

The proteasome is responsible for the majority of protein degradation within eukaryotic cells and proteasome inhibitors have gained blockbuster status as anticancer drugs. Here, we introduce an analytical platform comprising reverse phase chromatography, intact protein mass spectrometry, and customized data analysis that allows a streamlined investigation of ...


Acc. Chem. Res., 48 (4), pp 976–985, DOI: 10.1021/ar5003973

Acc. Chem. Res., online article


While immunoglobulins are well-known for their characteristic ability to bind macromolecular antigens (i.e., as antibodies during an immune response), the lipocalins constitute a family of proteins whose role is the complexation of small molecules for various physiological processes. In fact, a number of low-molecular-weight substances in multicellular organisms ...


2015, published on 05.01.2015



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Chem. Commun., 2015, DOI: 10.1039/C5CC00843C, 51, 5334-5336 published on 20.02.2015
Chem. Commun., online article

Polycyclic tetramate macrolactams (PTMs) are a structurally, biomedically and biosynthetically intriguing class of bacterial metabolites. By combining parts of the machineries of different PTM biosynthetic pathways, we demonstrate for the first time the substrate promiscuity of a class of PTM tailoring enzymes, thereby facilitating the (bio)synthesis of butremycin.  


Nature Communications, 2015, doi:10.1038/ncomms7320, 6, Article number: 6320 published on 19.02.2015
Nature Communications, online article


The Clp protease complex degrades a multitude of substrates, which are engaged by a AAA+ chaperone such as ​ClpX and subsequently digested by the dynamic, barrel-shaped ​ClpP protease. Acyldepsipeptides (ADEPs) are natural product-derived antibiotics that activate ​ClpP for chaperone-independent protein digestion. Here we show that both protein and small-molecule ...


Nature Chemical Biology, 2015, doi:10.1038/nchembio.1751, published on 16.02.2015
Nature Chemical Biology, online article

Ribosome stalling at polyproline stretches is common and fundamental. In bacteria, translation ​elongation factor P (​EF-P) rescues such stalled ribosomes, but only when it is post-translationally activated. In Escherichia coli, activation of ​EF-P is achieved by (R)-β-lysinylation and hydroxylation of a conserved ​lysine. Here we have unveiled a markedly ...


J. Proteome Res., 14 (3), pp 1574–1586, DOI: 10.1021/pr5012608

J. Proteome Res., online article



Solid supported probes have proven to be an efficient tool for chemical proteomics. The kinobeads technology features kinase inhibitors covalently attached to Sepharose for affinity enrichment of kinomes from cell or tissue lysates. This technology, combined with quantitative mass spectrometry, is of particular interest for the profiling of kinase inhibitors. It ...


Angewandte Chemie, 2015, DOI: 10.1002/anie.201409325, Volume 54, Issue 12, pages 3598–3602, published on 28.01.2015
Angewandte Chemie, online article

Listeria monocytogenes is a devastating bacterial pathogen. Its virulence and intracellular stress tolerance are supported by caseinolytic protease P (ClpP), an enzyme that is conserved among bacteria. L. monocytogenes expresses two ClpP isoforms that are only distantly related by sequence and differ in catalysis, oligomerization, active-site composition, and ...


Beilstein J. Org. Chem. 2015, 11, 155‒161; DOI: 10.3762/bjoc.11.15

Beilstein J. Org. Chem., online article


The development of selective anticancer vaccines that provide enhanced protection against tumor recurrence and metastasis has been the subject of intense research in the scientific community. The tumor-associated glycoprotein MUC1 represents a well-established target for cancer immunotherapy and has been used for the construction of various synthetic vaccine ...


Chem. Commun., 2015, DOI: 10.1039/C4CC10304A, 51, 4001-4004 published on 19.01.2015
Chem. Commun., online article

The synthesis of novel, chignolin-derived peptides comprising the azobenzene photoswitch [3-(3-aminomethyl)phenylazo]phenylacetic acid (AMPP) is reported. Reversible photoswitching behavior led to folding into β-hairpin-like structures, as unequivocally demonstrated by CD, FT-IR and NMR spectroscopy.


Bioinformatics, 32 (9): 1417-1419, DOI:
Bioinformatics, online article


Summary: To enable mass spectrometry (MS)-based proteomic studies with poorly characterized organisms, we developed a computational workflow for the homology-driven assembly of a non-redundant reference sequence dataset. In the automated pipeline, translated DNA sequences (e.g. ESTs, RNA deep-sequencing data) are aligned to those of a closely related and fully ...


Biochemical Journal, 466 (1) 95-104; DOI: 10.1042/BJ20141003

Biochemical Journal, online article


Human glycodelin (Gd) is an abundant glycoprotein from the lipocalin family and is involved in crucial biological processes such as reproduction and immune reaction. In females and males, Gd is found in four distinct glycoforms–A, C, F and S–that arise from different N-linked oligosaccharide side chains at amino acid residues Asn28 and Asn63. We have expressed Gd ...


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