Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator.

Area of Science:

• Neuroscience
• Pharmacology
• Structural Biology

Background:

• Neurotensin receptor 1 (NTSR1), a G protein-coupled receptor (GPCR), is involved in brain functions like dopamine modulation and feeding behavior.
• Biasing NTSR1 signaling towards β-arrestin pathways shows potential for attenuating psychostimulant and drug abuse effects.

Purpose of the Study:

• To determine the cryo-electron microscopy (cryo-EM) structures of NTSR1 in complex with Gq and GoA G proteins.
• To investigate the allosteric modulation of NTSR1 by the small molecule SBI-553 and its impact on G protein and β-arrestin signaling.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to resolve ternary complex structures.
• Functional assays to assess G protein and β-arrestin signaling.
• Structure-based analysis of allosteric binding sites.

Main Results:

• Cryo-EM structures of NTSR1-Gq and NTSR1-GoA complexes were obtained, with and without SBI-553.
• SBI-553 demonstrated complex allosteric modulation: negative allosteric modulation for Gα subunit-selective G proteins and positive allosteric modulation/agonism for β-arrestin translocation.
• Structural analysis identified the binding site and determinants for SBI-553's biased allosteric modulation.

Conclusions:

• The study provides structural insights into NTSR1 activation and biased allosteric modulation by SBI-553.
• Understanding these mechanisms can inform the development of novel therapeutics targeting NTSR1 for conditions like drug abuse.