Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism

• DOI: 10.1126/sciadv.abe5504
• Publication Date: 2021-01-27T20:16:37Z
• Authors: Mattia Deluigi; Alexander Klipp; Christoph Klenk; Lisa Merklinger; Stefanie A. Eberle; Lena Morstein; Philipp Heine; Peer R. E. Mittl; Patrick Ernst; Theodore M. Kamen...; Yuanjun He; Santiago Vacca; Pascal Egloff; Annemarie Honegger; Andreas Plückthun
• Keywords: Inverse agonist; Neurotensin receptor; Endogenous agonist

Neurotensin receptor 1 (NTSR1) and related G protein-coupled receptors of the ghrelin family are clinically unexploited, several mechanistic aspects their activation inactivation have remained unclear. Enabled by a new crystallization design, we present five structures: apo-state NTSR1 as well complexes with nonpeptide inverse agonists SR48692 SR142948A, partial agonist RTI-3a, novel full SRI-9829, providing structural rationales on how ligands modulate NTSR1. The favor large extracellular opening helices VI VII, undescribed so far for NTSR1, causing constriction intracellular portion. In contrast, induce binding site contraction, efficacy correlates ability to mimic mode endogenous neurotensin. Providing evidence helical side-chain rearrangements modulating activation, our functional data expand understanding potentially other peptidergic receptors.