6Z4Q

Crystal structure of the neurotensin receptor 1 in complex with the small-molecule inverse agonist SR142948A

これはPDB形式変換不可エントリーです。

6Z4Q の概要

• エントリーDOI: 10.2210/pdb6z4q/pdb
• 関連するPDBエントリー: 6YVR
• 分子名称: 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)
• 機能のキーワード: gpcr-ligand complex, rntsr1, sr142948a, inverse agonist, membrane protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53775.07

構造登録者

Deluigi, M.,Klipp, A.,Hilge, M.,Merklinger, L.,Klenk, C.,Plueckthun, A. (登録日: 2020-05-25, 公開日: 2021-02-10, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.923 Å)