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Structure paper

TitlePositive allosteric mechanisms of adenosine A receptor-mediated analgesia.
Journal, issue, pagesNature, Vol. 597, Issue 7877, Page 571-576, Year 2021
Publish dateSep 8, 2021
AuthorsChristopher J Draper-Joyce / Rebecca Bhola / Jinan Wang / Apurba Bhattarai / Anh T N Nguyen / India Cowie-Kent / Kelly O'Sullivan / Ling Yeong Chia / Hariprasad Venugopal / Celine Valant / David M Thal / Denise Wootten / Nicolas Panel / Jens Carlsson / Macdonald J Christie / Paul J White / Peter Scammells / Lauren T May / Patrick M Sexton / Radostin Danev / Yinglong Miao / Alisa Glukhova / Wendy L Imlach / Arthur Christopoulos /
PubMed AbstractThe 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 ...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.
External linksNature / PubMed:34497422 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 3.3 Å
Structure data

23280

7ld3

EMDB-23280, PDB-7ld3:
Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist and an allosteric ligand
Method: EM (single particle) / Resolution: 3.2 Å

23281

7ld4

EMDB-23281, PDB-7ld4:
Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-ADN:
ADENOSINE / Adenosine

ChemComp-XTD:
{2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiophen-3-yl}(4-chlorophenyl)methanone

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / membrane protein / active-state G protein-coupled receptor / adenosine A1 receptor / PAM / allosteric modulator

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