6Z4Q
Crystal structure of the neurotensin receptor 1 in complex with the small-molecule inverse agonist SR142948A
This is a non-PDB format compatible entry.
Summary for 6Z4Q
| Entry DOI | 10.2210/pdb6z4q/pdb |
| Related | 6YVR |
| Descriptor | Neurotensin receptor type 1,Neurotensin receptor type 1,DARPin, 2-[[5-(2,6-dimethoxyphenyl)-1-[4-[3-(dimethylamino)propyl-methyl-carbamoyl]-2-propan-2-yl-phenyl]pyrazol-3-yl]carbonylamino]adamantane-2-carboxylic acid (2 entities in total) |
| Functional Keywords | gpcr-ligand complex, rntsr1, sr142948a, inverse agonist, membrane protein |
| Biological source | Rattus norvegicus (Rat) More |
| Total number of polymer chains | 1 |
| Total formula weight | 53775.07 |
| Authors | Deluigi, M.,Klipp, A.,Hilge, M.,Merklinger, L.,Klenk, C.,Plueckthun, A. (deposition date: 2020-05-25, release date: 2021-02-10, Last modification date: 2024-10-23) |
| 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 Cited by 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: 33571132DOI: 10.1126/sciadv.abe5504 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.923 Å) |
Structure validation
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