| Title: |
Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism |
| Authors: |
Deluigi, Mattia; Klipp, Alexander; Klenk, Christoph; Merklinger, Lisa; Eberle, Stefanie A; Morstein, Lena; Heine, Philipp; Mittl, Peer R E; Ernst, Patrick; Kamenecka, Theodore M; He, Yuanjun; Vacca, Santiago; Egloff, Pascal; Honegger, Annemarie; Plückthun, Andreas |
| Source: |
Deluigi, Mattia; Klipp, Alexander; Klenk, Christoph; Merklinger, Lisa; Eberle, Stefanie A; Morstein, Lena; Heine, Philipp; Mittl, Peer R E; Ernst, Patrick; Kamenecka, Theodore M; He, Yuanjun; Vacca, Santiago; Egloff, Pascal; Honegger, Annemarie; Plückthun, Andreas (2021). Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism. Science Advances, 7(5):eabe5504. |
| Publisher Information: |
American Association for the Advancement of Science |
| Publication Year: |
2021 |
| Collection: |
University of Zurich (UZH): ZORA (Zurich Open Repository and Archive |
| Subject Terms: |
Department of Biochemistry; 570 Life sciences; biology; 610 Medicine & health |
| Description: |
Neurotensin receptor 1 (NTSR1) and related G protein-coupled receptors of the ghrelin family are clinically unexploited, and several mechanistic aspects of their activation and inactivation have remained unclear. Enabled by a new crystallization design, we present five new structures: apo-state NTSR1 as well as complexes with nonpeptide inverse agonists SR48692 and SR142948A, partial agonist RTI-3a, and the novel full agonist SRI-9829, providing structural rationales on how ligands modulate NTSR1. The inverse agonists favor a large extracellular opening of helices VI and VII, undescribed so far for NTSR1, causing a constriction of the intracellular portion. In contrast, the full and partial agonists induce a binding site contraction, and their efficacy correlates with the ability to mimic the binding mode of the endogenous agonist neurotensin. Providing evidence of helical and side-chain rearrangements modulating receptor activation, our structural and functional data expand the mechanistic understanding of NTSR1 and potentially other peptidergic receptors. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
2375-2548 |
| Relation: |
https://www.zora.uzh.ch/id/eprint/209842/1/Deluigi_et_al._2021.pdf; info:pmid/33571132; urn:issn:2375-2548 |
| DOI: |
10.1126/sciadv.abe5504 |
| Availability: |
https://www.zora.uzh.ch/id/eprint/209842/; https://www.zora.uzh.ch/id/eprint/209842/1/Deluigi_et_al._2021.pdf; https://doi.org/10.1126/sciadv.abe5504 |
| Rights: |
info:eu-repo/semantics/openAccess ; Creative Commons: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) ; http://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.85347CA0 |
| Database: |
BASE |