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

Publication ,  Journal Article
Krumm, BE; DiBerto, JF; Olsen, RHJ; Kang, HJ; Slocum, ST; Zhang, S; Strachan, RT; Huang, X-P; Slosky, LM; Pinkerton, AB; Barak, LS; Caron, MG ...
Published in: Biochemistry
April 4, 2023

The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward β-arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here, we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and GoA with and without the brain-penetrant small-molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Gα subunit selective and positive allosteric modulation and agonism for β-arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1.

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Published In

Biochemistry

DOI

EISSN

1520-4995

Publication Date

April 4, 2023

Volume

62

Issue

7

Start / End Page

1233 / 1248

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptors, Neurotensin
  • Peptides
  • Neurotensin
  • Biochemistry & Molecular Biology
  • 3404 Medicinal and biomolecular chemistry
  • 3205 Medical biochemistry and metabolomics
  • 3101 Biochemistry and cell biology
  • 1101 Medical Biochemistry and Metabolomics
 

Citation

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Krumm, B. E., DiBerto, J. F., Olsen, R. H. J., Kang, H. J., Slocum, S. T., Zhang, S., … Roth, B. L. (2023). Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator. Biochemistry, 62(7), 1233–1248. https://doi.org/10.1021/acs.biochem.3c00029
Krumm, Brian E., Jeffrey F. DiBerto, Reid H. J. Olsen, Hye Jin Kang, Samuel T. Slocum, Shicheng Zhang, Ryan T. Strachan, et al. “Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator.Biochemistry 62, no. 7 (April 4, 2023): 1233–48. https://doi.org/10.1021/acs.biochem.3c00029.
Krumm BE, DiBerto JF, Olsen RHJ, Kang HJ, Slocum ST, Zhang S, et al. Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator. Biochemistry. 2023 Apr 4;62(7):1233–48.
Krumm, Brian E., et al. “Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator.Biochemistry, vol. 62, no. 7, Apr. 2023, pp. 1233–48. Pubmed, doi:10.1021/acs.biochem.3c00029.
Krumm BE, DiBerto JF, Olsen RHJ, Kang HJ, Slocum ST, Zhang S, Strachan RT, Huang X-P, Slosky LM, Pinkerton AB, Barak LS, Caron MG, Kenakin T, Fay JF, Roth BL. Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator. Biochemistry. 2023 Apr 4;62(7):1233–1248.
Journal cover image

Published In

Biochemistry

DOI

EISSN

1520-4995

Publication Date

April 4, 2023

Volume

62

Issue

7

Start / End Page

1233 / 1248

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptors, Neurotensin
  • Peptides
  • Neurotensin
  • Biochemistry & Molecular Biology
  • 3404 Medicinal and biomolecular chemistry
  • 3205 Medical biochemistry and metabolomics
  • 3101 Biochemistry and cell biology
  • 1101 Medical Biochemistry and Metabolomics