A5075892383- Estrogen and related hormone effects
- Enzyme Catalysis and Immobilization
- Prostate Cancer Treatment and Research
- Fibroblast Growth Factor Research
- Computational Drug Discovery Methods
- Enzyme Production and Characterization
- Hormonal Regulation and Hypertension
- Ubiquitin and proteasome pathways
- Cellular transport and secretion
- Biofuel production and bioconversion
- Cholesterol and Lipid Metabolism
- Lipid Membrane Structure and Behavior
- Enzyme-mediated dye degradation
- Cancer, Hypoxia, and Metabolism
- Hippo pathway signaling and YAP/TAZ
- Photosynthetic Processes and Mechanisms
- Enzyme Structure and Function
- Microbial Metabolic Engineering and Bioproduction
- RNA and protein synthesis mechanisms
- Peptidase Inhibition and Analysis
- Hormonal and reproductive studies
- Protein Degradation and Inhibitors
- Protein Structure and Dynamics
- Lipid metabolism and biosynthesis
- Advanced Proteomics Techniques and Applications
Bayer (Germany)
2023
Orion Corporation (Finland)
2013-2022
Orion Corporation (United Kingdom)
2004-2017
University of Cologne
2000-2004
KTH Royal Institute of Technology
2003
École Polytechnique Fédérale de Lausanne
2002
VTT Technical Research Centre of Finland
1998-2001
Gesellschaft zur Förderung von Medizin-, Bio- und Umwelttechnologien
1999
Helmholtz Centre for Infection Research
1999
Abstract Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant (CRPC) dependent on functional AR and several mechanisms have been proposed to explain the addiction. Known causes CRPC include gene amplification overexpression as well point mutations AR. We report here pharmacological profile ODM-201, a novel inhibitor that showed significant antitumor activity favorable safety in phase 1/2 studies men with CRPC. ODM-201 full...
Glucose oxidase is a flavin-dependent enzyme which catalyses the oxidation of β-d-glucose by molecular oxygen to δ-gluconolactone and hydrogen peroxide. The structure from Aspergillus niger, previously refined at 2.3 Å resolution, has been 1.9 resolution an R value 19.0%, Penicillium amagasakiense, 65% sequence identity, determined replacement 1.8 16.4%. structures partially deglycosylated enzymes have r.m.s. deviation 0.7 for main-chain atoms show four N-glycosylation sites, with extended...
OSBP (oxysterol-binding protein) homologues, ORPs (OSBP-related proteins), constitute a 12-member family in mammals. We employed an vitro [3H]25OH (25-hydroxycholesterol)-binding assay with purified recombinant proteins as well live cell photo-cross-linking [3H]photo-25OH and [3H]photoCH (photo-cholesterol), to investigate sterol binding by the mammalian ORPs. ORP1 ORP2 [a short ORP consisting of ORD ligand-binding domain) only] were shown bind 25OH. GST (glutathione S-transferase) fusions...
Proteochemometric (PCM) modelling is a computational method to model the bioactivity of multiple ligands against related protein targets simultaneously.
Trichoderma reesei cellobiohydrolase Cel6A is an inverting glycosidase. Structural studies have established that the tunnel-shaped active site of contains two aspartic acids, D221 and D175, are close to glycosidic oxygen scissile bond at hydrogen-bonding distance from each other. Here, site-directed mutagenesis, X-ray crystallography, enzyme kinetic been used confirm role residue as catalytic acid. D175 shown affect protonation contribute electrostatic stabilization partial positive charge...
USP21 belongs to the ubiquitin-specific protease (USP) subfamily of deubiquitinating enzymes (DUBs). Due its relevance in tumor development and growth, has been reported as a promising novel therapeutic target for cancer treatment. Herein, we present discovery first highly potent selective inhibitor. Following high-throughput screening subsequent structure-based optimization, identified BAY-805 be non-covalent inhibitor with low nanomolar affinity high selectivity over other DUB targets well...
Abstract Deubiquitinases (DUBs) have recently become of high interest as some members this protein class show potential for therapeutic interventions. The family nearly 100 is divided into 6 sub families. Their action the cleavage ubiquitin modifications from proteins, by which function respective can change significantly. Due to catalytic reaction all DUBs share, it not clear so far how good specificity with small molecule inhibitors (SMOLs) be achieved. Until today, only a handful...
Both an active enzyme conformation and stabilization of tetrahedral transition states are essential for the catalysis ester bond hydrolysis by lipases. X-ray structural data results from site-directed mutagenesis experiments with proteases have been used as a basis predictions amino acid residues likely to key functions in The gene encoding lipase Rhizopus oryzae was cloned expressed Escherichia coli. Site-directed this test validity computer-aided functional roles specific acids enzyme....
The fungus Rhizopus oryzae synthesizes an extracellular lipase precursor bearing N-terminal pre- and pro-sequences. Our studies in Escherichia coli using recombinant vitro indicate that the prosequence of 97 amino acids has at least two functions. First, it modulates enzyme activity so this can initially be synthesized a non-destructive form. Direct synthesis mature form cell toxic consequences, partly because phospholipase is suppressed proprotein. Secondly, supports folding via pathway...
The plasma phospholipid transfer protein (PLTP) is an important regulator of high density lipoprotein (HDL) metabolism. We have here, based on sequence alignments the LPS-binding/lipid family and X-ray structure bactericidal/permeability increasing (BPI), modeled PLTP. model predicts a two-domain architecture with conserved lipid-binding pockets consisting apolar residues in each domain. By site-directed mutagenesis selected amino acid transient expression variants HeLa cells, are shown to...
The effects of mutation key conserved active-site residues (Tyr-73, Phe-418, Trp-430, Arg-516, Asn-518, His-520 and His-563) glucose oxidase from Penicillium amagasakiense on substrate binding were investigated. Kinetic studies the oxidation β-D-glucose combined with molecular modelling showed side chain which forms two hydrogen bonds 3-OH group β-D-glucose, to be absolutely essential for efficient β-D-glucose. R516K variant, whose only one bond exhibits an 80-fold higher apparent Km (513...
The crystal structures of Family 7 glycohydrolases suggest that a histidine residue near the acid/base catalyst could account for higher pH optimum Humicola insolens endoglucanase Cel7B, than corresponding Trichoderma reesei enzymes. Modelling studies indicated introduction at homologous position in T. Cel7A (Ala224) required additional changes to accommodate bulkier side chain. X-ray crystallography catalytic domain E223S/A224H/L225V/T226A/D262G mutant reveals major differences from...
The effects of mutation key conserved active-site residues (Tyr-73, Phe-418, Trp-430, Arg-516, Asn-518, His-520 and His-563) glucose oxidase from Penicillium amagasakiense on substrate binding were investigated. Kinetic studies the oxidation β-D-glucose combined with molecular modelling showed side chain which forms two hydrogen bonds 3-OH group β-D-glucose, to be absolutely essential for efficient β-D-glucose. R516K variant, whose only one bond exhibits an 80-fold higher apparent Km (513...
Abstract Background Prostate‐specific antigen (PSA or KLK3) has been shown to inhibit angiogenesis, but it might also have tumor promoting activities. Thus, may be possible modulate prostate cancer growth by stimulating inhibiting the activity of PSA. To this end we previously identified peptides that stimulate As several limitations as drug molecules, screened a chemical library find drug‐like compounds could used function(s) Methods Almost 50,000 were analyzed for their ability PSA towards...
Transcription factor GATA4 is a dosage sensitive regulator of heart development and alterations in its level or activity lead to congenital disease (CHD). has also been implicated cardiac regeneration repair. action involves combinatorial interaction with other cofactors such as NKX2-5, another critical whose mutations cause CHD. Despite importance the evolutionary conservation across species, structural basis GATA4-NKX2-5 remains incompletely understood.A homology model was constructed used...
Achieving selectivity for small organic molecules toward biological targets is a main focus of drug discovery but has been proven difficult, example, kinases because the high similarity their ATP binding pockets. To support design more selective inhibitors with fewer side effects or altered target profiles improved efficacy, we developed method combining ligand- and receptor-based information. Conventional QSAR models enable one to study interactions multiple ligands single protein target,...
Alterations in the gene encoding for FGFR and upregulation of VEGFR are found often cancer, which correlate with disease progression unfavorable survival. In addition, signaling synergistically promote tumor angiogenesis, activation has been described as functional compensatory angiogenic signal following development resistance to inhibition. Several selective small-molecule kinase inhibitors currently clinical development. ODM-203 is a novel, selective, equipotent inhibitor families. this...
Abstract Binding of steroid hormones to their cognate receptors regulates the growth most prostate and breast cancers. We hypothesized that CYP11A inhibition might halt synthesis all hormones, because is only enzyme catalyses first step hormone biosynthesis. speculated a inhibitor could be administered safely provided steroids essential for life are replaced. Virtual screening systematic structure–activity relationship optimization were used develop ODM-208, first-in-class, selective,...
Streptomyces griseus aminopeptidase (SGAP) is a double-zinc exopeptidase with high preference toward large hydrophobic amino-terminus residues. It monomer of relatively low molecular weight (30 kDa), it heat stable, displays and efficient catalytic turnover, its activity modulated by calcium ions. The small size, activity, stability make SGAP very attractive enzyme for various biotechnological applications, among which the processing recombinant DNA proteins fusion protein products. Several...