6ZIN

Crystal structure of the neurotensin receptor 1 in complex with the small molecule inverse agonist SR48692

This is a non-PDB format compatible entry.

Summary for 6ZIN

• Entry DOI: 10.2210/pdb6zin/pdb
• Descriptor: Neurotensin receptor type 1,DARPin,HRV 3C protease recognition sequence, 2-[[1-(7-chloranylquinolin-4-yl)-5-(2,6-dimethoxyphenyl)pyrazol-3-yl]carbonylamino]adamantane-2-carboxylic acid (2 entities in total)
• Functional Keywords: gpcr ligand complex, ntsr1, sr48692, inverse agonist, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 1
• Total formula weight: 53676.29

Authors

Deluigi, M.,Klipp, A.,Hilge, M.,Merklinger, L.,Klenk, C.,Plueckthun, A. (deposition date: 2020-06-26, release date: 2021-02-10, Last modification date: 2024-11-20)

Primary citation

Deluigi, M.,Klipp, A.,Klenk, C.,Merklinger, L.,Eberle, S.A.,Morstein, L.,Heine, P.,Mittl, P.R.E.,Ernst, P.,Kamenecka, T.M.,He, Y.,Vacca, S.,Egloff, P.,Honegger, A.,Pluckthun, A.
Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism.
Sci Adv, 7:-, 2021

PubMed Abstract: 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.

PubMed: 33571132
DOI: 10.1126/sciadv.abe5504

Experimental method

X-RAY DIFFRACTION (2.639 Å)