8FMZ

Neurotensin receptor allosterism revealed in complex with a biased allosteric modulator

Summary for 8FMZ

• Entry DOI: 10.2210/pdb8fmz/pdb
• EMDB information: 29301
• Descriptor: MiniGq, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, neurotensin receptor, allosterism, sbi-553, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 6
• Total formula weight: 150284.66

Authors

Krumm, B.E.,Diberto, J.F.,Olsen, R.H.J.,Kang, H.,Slocum, S.T.,Zhang, S.,Strachan, R.T.,Fay, J.F.,Roth, B.L. (deposition date: 2022-12-26, release date: 2023-03-29, Last modification date: 2024-10-30)

Primary citation

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.
Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator.
Biochemistry, 62:1233-1248, 2023

PubMed 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.

PubMed: 36917754
DOI: 10.1021/acs.biochem.3c00029

Experimental method

ELECTRON MICROSCOPY (2.59 Å)