A5070829764- Amino Acid Enzymes and Metabolism
- Enzyme Structure and Function
- SARS-CoV-2 and COVID-19 Research
- Protein Structure and Dynamics
- Virus-based gene therapy research
- Bacteriophages and microbial interactions
- Metabolism and Genetic Disorders
- Monoclonal and Polyclonal Antibodies Research
- Cancer, Hypoxia, and Metabolism
- Mitochondrial Function and Pathology
- SARS-CoV-2 detection and testing
- DNA Repair Mechanisms
- Bacterial Genetics and Biotechnology
- Drug Transport and Resistance Mechanisms
- Diet and metabolism studies
- Cancer-related Molecular Pathways
- Signaling Pathways in Disease
- Epigenetics and DNA Methylation
- Lipid Membrane Structure and Behavior
- Tuberculosis Research and Epidemiology
- ATP Synthase and ATPases Research
- Cellular transport and secretion
- Alcoholism and Thiamine Deficiency
- Cancer Research and Treatments
- Neuropeptides and Animal Physiology
University of Zurich
2022-2025
University of Groningen
2017-2024
Institute of Molecular Life Sciences
2020
Lomonosov Moscow State University
2014-2016
Engelhardt Institute of Molecular Biology
2016
The human Alanine Serine Cysteine Transporter 2 (ASCT2) is a neutral amino acid exchanger that belongs to the solute carrier family 1 (SLC1A). SLC1A structures have revealed an elevator-type mechanism, in which substrate translocated across cell membrane by large displacement of transport domain, whereas small movement hairpin (HP2) gates extracellular access substrate-binding site. However, it has remained unclear how binding and release gated on cytoplasmic side. Here, we present...
Article7 March 2022Open Access Transparent process Biparatopic sybodies neutralize SARS-CoV-2 variants of concern and mitigate drug resistance Justin D Walter orcid.org/0000-0002-1492-3055 Institute Medical Microbiology, University Zurich, Switzerland Contribution: Conceptualization, Supervision, Investigation, Visualization, Methodology, Writing - original draft, review & editing Search for more papers by this author Melanie Scherer orcid.org/0000-0001-5554-9664 Division Neurological...
Significance The glutamine transporter ASCT2 is an emerging therapeutic target for various cancer types. Here, we use integrated computational and experimental approach to develop unique inhibitors targeting a conformational state useful rational drug design. We apply chemistry tools such as molecular docking dynamics simulations, in combination with structure determination cryo-electron microscopy synthetic chemistry, design multiple inhibitors. Our results reveal mechanism of...
We found that inhibitors of mitochondrial respiratory chain complexes III (myxothiazol) and I (piericidin A) in some epithelial carcinoma cell lines induce transcription the p53-responsive SESN2 gene plays an important role stress response homeostatic regulation. However, effect did not depend on p53 because i) there was no induction after treatment with piericidin A; ii) myxothiazol peak upregulation occurred as early 5h, before onset activation (13h); iii) a supplementation uridine...
The multiple peptide resistance factor (MprF) is a bifunctional membrane protein found in many bacteria, including Pseudomonas aeruginosa and Staphylococcus aureus . MprF modifies inner leaflet lipid headgroups through aminoacylation translocates modified to the outer leaflet. This activity provides increased antimicrobial agents. presents promising target multiresistant pathogens, but structural information limited both substrate specificity energization of MprF-mediated transport are...
Abstract Generation of energy in mitochondria is subjected to physiological regulation at many levels, and its malfunction may result mitochondrial diseases. Mitochondrial dysfunction associated with different environmental influences or certain genetic conditions, can be artificially induced by inhibitors acting steps the electron transport chain (ETC). We found that a short-term (5 h) inhibition ETC complex III myxothiazol results phosphorylation translation initiation factor eIF2 α...
Abstract It is well-established that the secondary active transporters Glt Tk and Ph catalyze coupled uptake of aspartate three sodium ions, but insight in kinetic mechanism transport fragmentary. Here, we systematically measured rates proteoliposomes containing purified , derived rate equation for a which two ions bind before another after aspartate. Re-analysis existing data on using this allowed determination turnover number (0.14 s −1 ), without need error-prone protein quantification....
Membrane transporters of the bacterial pyridine nucleotide uptake (Pnu) family mediate various B-type vitamins. For example, PnuT have specificity for vitamin B1 (thiamine). It has been hypothesized that Pnu are facilitators allow passive transport substrate across membrane. Metabolic trapping by phosphorylation would then lead to accumulation transported substrates in cytoplasm. However, experimental evidence such a mechanism is lacking. Here, determine thiamine transport, we purify PnuTSw...
ASCT2 is an obligate exchanger of neutral amino acids, contributing to cellular acid homeostasis. belongs the same family (SLC1) as Excitatory Amino Acid Transporters (EAATs) that concentrate glutamate in cytosol. The mechanism makes rather than a concentrator remains enigmatic. Here, we employ cryo-electron microscopy and molecular dynamics simulations elucidate structural basis exchange ASCT2. We establish binds three Na+ ions per transported substrate visits state likely acts checkpoint...
ABSTRACT The ongoing COVID-19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair (Sb#15 and Sb#68) that can bind simultaneously to SARS-CoV-2 spike-RBD efficiently neutralize pseudotyped live-viruses by interfering with ACE2 interaction. Two spatially-discrete epitopes identified cryo-EM translated into rational design bispecific tri-bispecific fusions constructs, exhibiting up 100- 1000-fold increase in...
ABSTRACT ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls homeostasis in peripheral tissues. upregulated cancer, where it modulates intracellular glutamine levels, fueling cell proliferation. Nutrient deprivation via inhibition provides an emerging strategy for cancer therapy. Here, guided by homology model of outward-facing conformation, we rationally designed novel inhibitors exploiting stereospecific pockets the substrate binding site. A cryo-EM structure...
Background: ASCT2 protein belongs to Solute Carrier Family 1 (SLC1A) transporters and is a promising target for the development of anticancer antiretroviral drugs.It upregulated linked poor survival in melanoma, lung, breast, prostate, pancreatic, thyroid colon cancer serves as receptor simian retrovirus 4, feline endogenous virus, human type W baboon M7 virus.However, there lack structural functional characterization this protein.Methods: We used single particle cryo-electron microscopy...