7LD3

Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist and an allosteric ligand

7LD3 の概要

• エントリーDOI: 10.2210/pdb7ld3/pdb
• EMDBエントリー: 23280
• 分子名称: Guanine nucleotide-binding protein G(i) subunit alpha-2, Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• 機能のキーワード: signaling protein, membrane protein, active-state g protein-coupled receptor, adenosine a1 receptor, pam, allosteric modulator
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 130876.13

構造登録者

Draper-Joyce, C.J.,Danev, R.,Thal, D.M.,Christopoulos, A.,Glukhova, A. (登録日: 2021-01-12, 公開日: 2021-09-08, 最終更新日: 2024-11-13)

主引用文献

Draper-Joyce, C.J.,Bhola, R.,Wang, J.,Bhattarai, A.,Nguyen, A.T.N.,Cowie-Kent, I.,O'Sullivan, K.,Chia, L.Y.,Venugopal, H.,Valant, C.,Thal, D.M.,Wootten, D.,Panel, N.,Carlsson, J.,Christie, M.J.,White, P.J.,Scammells, P.,May, L.T.,Sexton, P.M.,Danev, R.,Miao, Y.,Glukhova, A.,Imlach, W.L.,Christopoulos, A.
Positive allosteric mechanisms of adenosine A 1 receptor-mediated analgesia.
Nature, 597:571-576, 2021

PubMed Abstract: The adenosine A receptor (AR) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain. However, development of analgesic orthosteric AR agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the AR, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the AR co-bound to adenosine, MIPS521 and a G heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.

PubMed: 34497422
DOI: 10.1038/s41586-021-03897-2

実験手法

ELECTRON MICROSCOPY (3.2 Å)