Faculty Opinions recommendation of Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile).

2015 ◽  
Author(s):  
John Lowe
Keyword(s):  
Drug Discovery ◽  
Allosteric Modulator ◽  
Negative Allosteric Modulator ◽  
Class C

scholarly journals Structure of a Class C GPCR Metabotropic Glutamate Receptor 1 Bound to an Allosteric Modulator

Science ◽  
2014 ◽  
Vol 344 (6179) ◽  
pp. 58-64 ◽  
Author(s):  
Huixian Wu ◽  
Chong Wang ◽  
Karen J. Gregory ◽  
Gye Won Han ◽  
Hyekyung P. Cho ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Full Length ◽  
Activation Mechanism ◽  
Allosteric Modulator ◽  
Excitatory Neurotransmitter ◽  
Metabotropic Glutamate ◽  
Metabotropic Glutamate Receptor 1 ◽  
Negative Allosteric Modulator ◽  
Class C

The excitatory neurotransmitter glutamate induces modulatory actions via the metabotropic glutamate receptors (mGlus), which are class C G protein–coupled receptors (GPCRs). We determined the structure of the human mGlu1 receptor seven-transmembrane (7TM) domain bound to a negative allosteric modulator, FITM, at a resolution of 2.8 angstroms. The modulator binding site partially overlaps with the orthosteric binding sites of class A GPCRs but is more restricted than most other GPCRs. We observed a parallel 7TM dimer mediated by cholesterols, which suggests that signaling initiated by glutamate’s interaction with the extracellular domain might be mediated via 7TM interactions within the full-length receptor dimer. A combination of crystallography, structure-activity relationships, mutagenesis, and full-length dimer modeling provides insights about the allosteric modulation and activation mechanism of class C GPCRs.

scholarly journals GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors

2017 ◽  
Vol 123 ◽  
pp. 322-331 ◽  
Author(s):  
Brice Mullier ◽  
Christian Wolff ◽  
Zara Amanda Sands ◽  
Philippe Ghisdal ◽  
Pierandrea Muglia ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Allosteric Modulator ◽  
Gain Of Function ◽  
Negative Allosteric Modulator

scholarly journals The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Christopher J. Draper-Joyce ◽  
Ravi Kumar Verma ◽  
Mayako Michino ◽  
Jeremy Shonberg ◽  
Anitha Kopinathan ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Allosteric Modulator ◽  
Sodium Ions ◽  
Dopamine D2 ◽  
Negative Allosteric Modulator
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