The adenosine A1 receptor (A1R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects3. 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 A1R, 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 A1R co-bound to adenosine, MIPS521 and a Gi2 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.
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Cryo-EM coordinates have been deposited in the PDB under the accession codes 7LD3 (MIPS521- and ADO-bound A1R–Gi2 complex) and 7LD4 (ADO-bound A1R–Gi2 complex); the corresponding electron microscopy maps have been deposited in the Electron Microscopy Data Bank (EMDB) under accession codes EMD-23280 and EMD-23281.
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This work was supported by the National Health and Medical Research Council of Australia (NHMRC) project grants 1145420 and 1147291, NHMRC program grant 1050083, American Heart Association grant 17SDG33370094 and the National Institutes of Health grant R01GM132572. P.M.S., W.L.I. and D.W. are NHMRC Senior Principal Research, Career Development and Senior Research Fellows, respectively. C.J.D.-J., A.G. and D.M.T. are Australian Research Council Discovery Early Career Research Fellows. L.T.M. is an Australian Heart Foundation Future Leaders Fellow. J.C. acknowledges support from the Swedish Research Council (2017-04676). We are grateful to S. Charman and K. White for performing the VCP171 and MIPS521 plasma and liver microsome stability studies. We acknowledge use of facilities within the Monash Ramaciotti Cryo-EM platform. This work was supported by the MASSIVE HPC facility (https://www.massive.org.au) and the Extreme Science and Engineering Discovery Environment supercomputing award TG-MCB180049.
The authors declare no competing interests.
Peer review information Nature thanks Grégory Scherrer, Irina Tikhonova, Daniel Wacker and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Extended data figures and tables
Extended Data Fig. 1 Physiological effects of VCP171 and MIPS521.
a, Chemical structure of VCP171. b, Time courses of paw withdrawal threshold (PWT) to mechanical stimulus by von Frey filaments in nerve-injured rats post-intrathecal administration of VCP171 (blue) or MIPS521 (red). Significance to vehicle control was determined using Greenhouse-Geisser correction for multiple comparisons, corrected with Dunnett’s post-hoc test, * P < 0.05, ** P < 0.01, *** P < 0.001. Data are shown as mean +/- SEM (n=8-10 rats per data group) c, Single trial place preference conditioning with intrathecal VCP171 (30 µg, blue), MIPS521 (10 µg, red) and morphine (10 µg, black) increased the time nerve-injured rats spent in the drug paired chamber, with a corresponding decrease in the vehicle paired chamber. Sham surgery rats showed no chamber preference. Empty circles show individual data points, and bars show mean +SEM (n = 8 per group). Significance was determined using a two-tailed unpaired t test assuming unequal variance, * P < 0.05, ** P < 0.01, compared to vehicle control. d, Rotarod latency in rats following intrathecal administration of VCP171 (blue) or MIPS521 (red) is not significantly different to vehicle controls, whereas intrathecal administration of morphine reduces rotarod latency to fall. Data are shown as mean +/- SEM (n = 3-4 per group). Significance was determined using a two-tailed unpaired t test assuming unequal variance, * P < 0.05, ** P < 0.01, compared to vehicle control. e, Effect of CPA (black; n = 4) or MIPS521 (solid red; n = 6) on rate of atrial contraction. Data represent mean ± SD.
Extended Data Fig. 2
Effects of VCP171 and MIPS521 on spontaneous excitatory synaptic activity. a, Examples of spontaneous excitatory postsynaptic potentials (sEPSCs) recorded from neurons of the superficial laminae of the spinal dorsal horn of nerve-injured rats. b, sEPSC frequency and amplitude were reduced following superfusion of VCP171 or MIPS521, which is reversed by the antagonist, DPCPX (n = 8 per group). Significance compared to baseline was determined using a two-tailed paired t test, *P < 0.05, **P < 0.01.
Extended Data Fig. 3 Expression and purification of the MIPS521–ADO–A1R–Gi2 complex.
a, Expression and purification flowchart for the A1R–Gi2 complex. A1R and the Gi2 heterotrimer with Gβ1γ2 were expressed separately in insect cell membranes. Addition of ADO (1 mM) and MIP521 (100 nM) initiated complex formation, which was solubilized with 0.5% (w/v) lauryl maltose neopentyl glycol and 0.05% (w/v) cholesteryl hemisuccinate. Solubilized A1R and A1R –Gi2 complex was immobilized on Flag antibody resin. Flag-eluted fractions were purified by size-exclusion chromatography (SEC). Illustrations taken from ChemDraw. b, SDS–PAGE/western blot of the purified A1R–Gi2 complex. An anti-His antibody was used to detect Flag–A1R-His and Gβ1-His (red) and an anti-Gi2 antibody was used to detect Gαi2 (green). For gel source data, see Supplementary Fig. 1. c, SDS–PAGE/Coomassie blue stain of the purified complex concentrated from the Superdex 200 Increase 10/30 column. For gel source data, see Supplementary Fig. 1. d, Representative elution profile of Flag-purified complex on Superdex 200 Increase 10/30 SEC.
Extended Data Fig. 4 Cryo-EM data processing for the MIPS521–ADOβ–A1R–Gi2 and ADO–A1R–Gi2 complexes.
a, MIPS521–ADOβ–A1R–Gi2; b, ADO–A1R–Gi2. Representative cryo-EM micrographs of each of the complexes. Reference-free 2D class averages of the complexes in LMNG and CHS detergent micelles. Gold-standard Fourier shell correlation (FSC) curves, showing the overall nominal resolution of 3.2 Å and 3.3 Å, respectively, at FSC 0.143. Corresponding 3D cryo-EM maps coloured according to local resolution estimation (Å) in Relion. c, Atomic resolution model of representative regions from the MIPS521-ADO-A1R-Gi2 structure of the A1R transmembrane domain, ADO, and MIPS521. The molecular model is shown in ball and stick representation, coloured by heteroatom, and the cryo-EM map displayed in mesh contoured at 0.02.
Extended Data Fig. 5 Stable hydrogen bonds formed between residue S6.47/L7.41 in A1R and MIPS521 in A1R–Gi2–MIPS521.
a, c, GaMD and b, d, cMD simulations. Each simulation trace is displayed in a different colour (black, red, blue). The lines depict the running average over 2 ns.
Extended Data Fig. 6 Affinity of orthosteric ligands at mutations of the MIPS521 extrahelical allosteric binding pocket.
a, c, The affinity of (a) [3H]-DPCPX and (c) NECA for wildtype and mutant A1Rs performed in FlpInCHO cells. b, Bmax; determined by [3H]-DPCPX radioligand saturation binding studies. Data are the means + S.E.M. of 3-7 independent experiments (shown as circles) performed in duplicate. *P < 0.05 (compared with WT; one-way analysis of variance, Dunnett’s post-hoc test).
Extended Data Fig. 7 Extrahelical binding sites for allosteric modulators of class A GPCRs.
The unique extrahelical binding pose of MIPS521 in the A1R (orange) compared to previously reported extrahelical allosteric binding pockets for class A GPCRs in P2Y1R (BPTU, red; PDB 4XNV), PAR2 (AZ3451, yellow; PDB 5NDZ), CB1 (ORG28569, green; 6KQI), GPR40 (AP8, cyan; PDB 5TZY), C5aR (NDT9513727, blue; PDB 5O9H), D1R (LY3154207, navy; PDB 7LJD), and β2AR (Compound-6FA, pink; PDB 6N48).
Extended Data Fig. 8 Stability of MIPS521 at the allosteric binding site of A1R is enhanced by Gi2 protein coupling to the receptor.
a, b, RMSD (Å) of MIPS521 relative to the starting cryo-EM conformation obtained from GaMD simulations in the (a) absence and (b) presence of Gi2. c, d, RMSD (Å) of MIPS521 relative to the starting cryo-EM conformation obtained from cMD simulations in the (c) absence and (d) presence of Gi2. Each condition represents three GaMD/cMD simulations, with each simulation trace displayed in a different colour (black, red, blue). Lines depict the running average over 2 ns.
Extended Data Fig. 9 MIPS521 stabilizes the A1R–Gi2 ternary complex.
a–d, RMSD (Å) of ADO from cMD simulations completed in the (a) absence or (b) presence of MIPS521, (c) Gi2, or (d) both Gi2 and MIPS521. e–h, Distance between the intracellular ends of TM3 and TM6 (measured as the distance in Å between Arg1053.50 and Glu2296.30) in the (e) absence or (f) presence of MIPS521, (g) Gi2, or (h) both Gi2 and MIPS521. Each condition represents three cMD simulations, with each simulation trace displayed in a different colour (black, red, blue). The lines depict the running average over 2 ns. i, j, Distance between A1R and Gi2 (measured as the distance in Å between the NPxxY motif of A1R and the C terminus of the Gα α5 helix) from GaMD simulations in the (i) absence and (j) presence of MIPS521. k, l, Distance between A1R and Gi2 from cMD simulations in the (k) absence and (l) presence of MIPS521. Each condition represents three GaMD/cMD simulations, with each simulation trace displayed in a different colour (black, red, blue). Thick lines depict the running average over 2 ns. m–p, Flexibility change upon removal of PAM and/or Gi2 protein from the ADO-bound A1R obtained from GaMD simulations.(m, RMSFs of the A1R-Gi2-MIPS521. A colour scale of 0.0 Å (blue) to 5.0 Å (red) was used. n, Change in the RMSFs of the A1R-Gi2 when MIPS521 was removed from A1R-Gi2-MIPS521. o, Change in the RMSFs of the A1R and MIPS521 when the Gi2 was removed from A1R-Gi2-MIPS521. p, Change in the RMSFs of the A1R when the Gi2 and MIPS521 were removed from A1R-Gi2-MIPS521 system. A colour scale of -2.0 Å (blue) to 2.0 Å (red) was used for n, o and p.
This file contains Supplementary Tables 1–6 and their accompanying legends.
Supplementary Figure 1
Original western and SDS–PAGE gels used to generate Extended Data Fig. 3b, c. Dotted boxes indicate the area of gel used.
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Draper-Joyce, C.J., Bhola, R., Wang, J. et al. Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia. Nature 597, 571–576 (2021). https://doi.org/10.1038/s41586-021-03897-2
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