Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator

Brian E. Krumm; Jeffrey F. DiBerto; Reid H.J. Olsen; Hye Jin Kang; Samuel T. Slocum; Shicheng Zhang; Ryan T. Strachan; Xi Ping Huang; Lauren M. Slosky; Anthony B. Pinkerton; Lawrence S. Barak; Marc G. Caron; Terry Kenakin; Jonathan F. Fay; Bryan L. Roth

doi:10.1021/acs.biochem.3c00029

Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator

Brian E. Krumm, Jeffrey F. DiBerto, Reid H.J. Olsen, Hye Jin Kang, Samuel T. Slocum, Shicheng Zhang, Ryan T. Strachan, Xi Ping Huang, Lauren M. Slosky, Anthony B. Pinkerton, Lawrence S. Barak, Marc G. Caron, Terry Kenakin, Jonathan F. Fay, Bryan L. Roth

Pharmacology

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1233-1248
Number of pages	16
Journal	Biochemistry
Volume	62
Issue number	7
DOIs	https://doi.org/10.1021/acs.biochem.3c00029
State	Published - Apr 4 2023

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© 2023 American Chemical Society

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Research Support, N.I.H., Extramural

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10.1021/acs.biochem.3c00029

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Krumm, B. E., DiBerto, J. F., Olsen, R. H. J., Kang, H. J., Slocum, S. T., Zhang, S., Strachan, R. T., Huang, X. P., Slosky, L. M., Pinkerton, A. B., Barak, L. S., Caron, M. G., Kenakin, T., Fay, J. F., & 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

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title = "Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator",

abstract = "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.",

author = "Krumm, {Brian E.} and DiBerto, {Jeffrey F.} and Olsen, {Reid H.J.} and Kang, {Hye Jin} and Slocum, {Samuel T.} and Shicheng Zhang and Strachan, {Ryan T.} and Huang, {Xi Ping} and Slosky, {Lauren M.} and Pinkerton, {Anthony B.} and Barak, {Lawrence S.} and Caron, {Marc G.} and Terry Kenakin and Fay, {Jonathan F.} and Roth, {Bryan L.}",

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doi = "10.1021/acs.biochem.3c00029",

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AU - Krumm, Brian E.

AU - DiBerto, Jeffrey F.

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AU - Kang, Hye Jin

AU - Slocum, Samuel T.

AU - Zhang, Shicheng

AU - Strachan, Ryan T.

AU - Huang, Xi Ping

AU - Slosky, Lauren M.

AU - Pinkerton, Anthony B.

AU - Barak, Lawrence S.

AU - Caron, Marc G.

AU - Kenakin, Terry

AU - Fay, Jonathan F.

AU - Roth, Bryan L.

PY - 2023/4/4

Y1 - 2023/4/4

N2 - 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.

AB - 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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Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator

Abstract

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