A5049028144- Neuropeptides and Animal Physiology
- Receptor Mechanisms and Signaling
- Monoclonal and Polyclonal Antibodies Research
- Chemical Synthesis and Analysis
- Chronic Lymphocytic Leukemia Research
- Viral-associated cancers and disorders
- Drug Transport and Resistance Mechanisms
- Diabetes Treatment and Management
- Hypothalamic control of reproductive hormones
- Protein Kinase Regulation and GTPase Signaling
- Peptidase Inhibition and Analysis
- Lymphoma Diagnosis and Treatment
University of Zurich
2014-2021
Significance Only a tiny fraction (<2%) of the unique structures in protein database correspond to membrane proteins, and only few these are eukaryotic origin, representing potential drug targets. The difficulties structure determination proteins due two specific complications, which for proteins: first, low expression levels and, second, necessity detergent micelles, often destabilizing as they mimic hydrophobic environment poorly. We prove that directed evolution has overcome problems...
Neurotensin receptor 1 (NTSR1) and related G protein-coupled receptors of the ghrelin family are clinically unexploited, several mechanistic aspects their activation inactivation have remained unclear. Enabled by a new crystallization design, we present five structures: apo-state NTSR1 as well complexes with nonpeptide inverse agonists SR48692 SR142948A, partial agonist RTI-3a, novel full SRI-9829, providing structural rationales on how ligands modulate NTSR1. The favor large extracellular...
The neurotensin receptor 1 represents an important drug target involved in various diseases of the central nervous system. So far, full exploitation potential therapeutic activities has been compromised by lack compounds with favorable physicochemical and pharmacokinetic properties which efficiently penetrate blood-brain barrier. Recent progress generation stabilized variants solubilized its subsequent purification successful structure determination presents a solid starting point to apply...
Peptide-recognizing G protein-coupled receptors (GPCRs) are promising therapeutic targets but often resist drug discovery efforts. Determination of crystal structures for peptide-binding GPCRs has provided opportunities to explore structure-based methods in lead development. Molecular docking screens two chemical libraries, containing either fragment- or lead-like compounds, against a neurotensin receptor 1 structure allowed comparison between different development strategies GPCRs. A total...
The development of cell-free high-throughput (HT) methods to screen and select novel lead compounds remains one the key challenges in G protein-coupled receptor (GPCR) drug discovery. Mutational approaches have allowed stabilization GPCRs a purified ligand-free state. increased intramolecular stability overcomes two major drawbacks for usage vitro screening, low density on cells micelles. Here, an HT fluorescence polarization (FP) assay neurotensin type 1 (NTS1) was developed. operates...