7LD4

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

Summary for 7LD4

• Entry DOI: 10.2210/pdb7ld4/pdb
• EMDB information: 23281
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-2, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: signaling protein, membrane protein, active-state g protein-coupled receptor, adenosine a1 receptor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 130426.33

Authors

Draper-Joyce, C.J.,Danev, R.,Thal, D.M.,Christopoulos, A.,Glukhova, A. (deposition date: 2021-01-12, release date: 2021-09-08, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.3 Å)