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Activation and allosteric modulation of a muscarinic acetylcholine receptor
The structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the β2AR and rhodopsin.
Structural insights into μ-opioid receptor activation
A 2.1 Å X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment is reported, revealing an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.
Structure-based discovery of opioid analgesics with reduced side effects
PZM21 is a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses.
Structure and Function of an Irreversible Agonist-β2 Adrenoceptor complex
A covalent agonist-bound β2AR–T4L fusion protein is designed that can be covalently tethered to a specific site on the receptor through a disulphide bond, and is capable of activating a heterotrimeric G protein.
Visualization and ligand-induced modulation of dopamine receptor dimerization at the single molecule level
Using TIRF microscopy at the single molecule level, transient formation of homodimers of dopamine receptors in the membrane of stably transfected CHO cells has been observed and the equilibrium between dimers and monomers was modulated by the binding of ligands.
Muscarinic Receptors as Model Targets and Antitargets for Structure-Based Ligand Discovery
The results support the ability of structure-based discovery to identify new ligands with unexplored chemotypes and physical properties, leading to new biologic functions, even in an area as heavily explored as muscarinic pharmacology.
Recent advances in the search for D3- and D4-selective drugs: probes, models and candidates.
Tricyclic antidepressants, quinacrine and a novel, synthetic chimera thereof clear prions by destabilizing detergent‐resistant membrane compartments
The data suggest that a cocktail of drugs targeting the lipid metabolism that controls PrP conversion may be the most efficient in treating Creutzfeldt‐Jakob disease.
Covalent molecular probes for class A G protein-coupled receptors: advances and applications.
This work reviews covalently binding molecular probes for class A GPCRs with a focus on ligands comprising cross-linking groups that do not require photoactivation and further highlight their significant and diverse applications.
Dopamine D2, D3, and D4 selective phenylpiperazines as molecular probes to explore the origins of subtype specific receptor binding.
- Katharina Ehrlich, Angela Götz, P. Gmeiner
- Biology, ChemistryJournal of Medicinal Chemistry
- 16 July 2009
These chemically similar but biologically divergent target compounds served as molecular probes for radioligand displacement experiments, mutagenesis, and docking studies on homology models based on the recent crystal structure of the beta2-adrenergic receptor.