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Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators

Nature Structural & Molecular Biology volume 24, pages 108–113 (2017)Cite this article

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Abstract

Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-Å resolution. AM-3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.

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Figure 1: In vitro profiling of AM-1488 on GlyRs and in vivo reversal of SNI-induced tactile allodynia after oral dosing.
Figure 2: In vitro profiling of AM-3607 on full-length and engineered human GlyR channels.
Figure 3: Architecture of the GlyRα3cryst N38Q in complex with glycine and AM-3607.
Figure 4: Neurotransmitter-binding site occupied by the agonist glycine.
Figure 5: Allosteric binding site occupied by AM-3607.

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Acknowledgements

We thank G. Ranieri and R. Walter at Shamrock Structures and the staff at beamline 22-ID at the Advanced Photon Source for data collection. We also thank V. Berry, L. Berry, M. Chaves, J. Hu, P. Pegman, N.K. Yelleswarapu, the Comparative Animal Research staff and the large team responsible for toxicology data acquisition for technical support. We are grateful to Z. Wang, A. Guzman-Perez, M. Chu-Moyer, T. Kornecook, Z. Kaprielian and K. Wild for critical review of the manuscript.

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Author notes

  1. Xin Huang and Paul L Shaffer: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, Massachusetts, USA

    Xin Huang, Paul L Shaffer & Shawn Ayube

  2. Department of Medicinal Chemistry, Amgen Inc., Cambridge, Massachusetts, USA

    Howard Bregman, Shuyan Yi & Erin F DiMauro

  3. Department of Protein Technologies, Amgen Inc., Cambridge, Massachusetts, USA

    Hao Chen

  4. Department of Neuroscience, Amgen Inc., Thousand Oaks, California, USA

    Sonya G Lehto & Maosheng Zhang

  5. Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, USA

    Jason A Luther, David J Matson, Stefan I McDonough, Stephen Schneider, Jeffrey R Simard & Jacinthe Gingras

  6. Department of Discovery Attribute Sciences, Amgen Inc., Cambridge, Massachusetts, USA

    Klaus Michelsen & Matthew H Plant

  7. Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., Cambridge, Massachusetts, USA

    Yohannes Teffera

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Contributions

The authors jointly contributed to project design, data analysis and manuscript preparation. P.L.S. performed initial construct design and purification experiments, structure solution, model building, structural analysis and ITC binding titrations; X.H. performed construct design, protein purifications, crystallization, structural solution, model building and structural analysis; H.C. performed cloning and expression experiments; H.B., S.Y. and E.F.D. designed and synthesized AM-3607 and AM-1488; S.A. purified AM-3607; J.R.S., S.S., J.A.L., D.J.M., S.I.M., M.Z., S.G.L. and J.G. performed functional studies; Y.T. performed the pharmacokinetic analysis; K.M. and M.H.P. performed SPR binding experiments; X.H., P.L.S., E.F.D. and J.G. wrote the manuscript with assistance from the other coauthors.

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Correspondence to Xin Huang, Paul L Shaffer, Erin F DiMauro or Jacinthe Gingras.

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Integrated supplementary information

Supplementary Figure 1 In vitro electrophysiological and binding characterization of AM-1488 and AM-3607 through IonFlux HT and SPR.

(a) AM-1488 potentiates currents evoked by EC20 glycine in HEK293T cells stably expressing human GlyRα3β (EC50 = 0.26 ± 0.02 μM), as shown by the dose response plotted as percent of maximal evoked current amplitude (1 mM glycine). (b) AM-3607 potentiates currents evoked by EC20 glycine in HEK293T cells stably expressing human GlyRα3β (EC50 = 0.051 ± 0.016 μM), as shown by the dose response plotted as percent of maximal evoked current amplitude (1 mM glycine). All values are calculated EC50 ± s.e.m. and each data point is mean ± s.e.m. with N≥5 for (a) and (b). (c) Representative binding trace of AM-1488 to GlyRα3cryst measured by SPR with kinetic fit overlaid. (d) Representative binding trace of AM-3607 to GlyRα3cryst measured by SPR with kinetic fit overlaid. Values for KD are mean ± s.d. determined from N=3 experiments for (c) and (d). (e) Representative trace of AM-1488 not binding to GlyRα3cryst preincubated with AM-3607 measured by SPR. Trace is representative of N=4 total trials on two different flow cells.

Supplementary Figure 2 In vivo evaluation of AM-1488 in a mouse open field assay.

(a) AM-1488 had no significant effect on the total basic movements (5708 ± 482 cm, N=10), when compared to the vehicle treated group (5052 ± 131 cm, N=10; t18 = 1.3, p > 0.05) at 60 min post oral dosing in naïve mice. (b) AM-1488 had slight reduction on total rearing counts (354 ± 137), when compared to the vehicle treated group (498 ± 149; t18 = 2.2, p < 0.05). All values are mean ± s.e.m. except Cu values which are mean ± s.d..

Supplementary Figure 3 Crystallographic packing of GlyRα3cryst.

(a) Packing of the GlyRα3–glycine–AM-3607 complex. Receptor in the assymmetric unit is colored by subunit, with subunit A in pale green and B in cyan. AM-3607 molecules are shown as slate spheres. Symmetry related receptors are colored grey. (b) Packing of the GlyRα3N38Q–glycine–AM-3607 complex. Receptor in the assymmetric unit is colored by subunit, with subunit A in pale green and B in cyan. AM-3607 molecules are shown as slate spheres. Symmetry related receptors are colored grey.

Supplementary Figure 4 Omit maps of the orthosteric binding site and the allosteric binding site occupied by the agonist glycine and AM-3607, respectively.

(a) 2Fo-Fc omit map of the orthosteric binding site viewed perpendicular to the plasma membrane contoured at 1σ. Glycine was omitted from the electron density map calculation and is shown as grey sticks. The principal or (+) subunit is colored in pale green and the complementary or (-) subunit is colored cyan. Important residues are noted. Black dashed line indicates hydrogen bonds. (b) 2Fo-Fc omit map of the allosteric binding site viewed parallel to the plasma membrane contoured at 1σ. AM-3607 was omitted from the electron density map calculations and is shown as slate sticks. (c) Fo-Fc omit map of the orthosteric binding site in same view as in (a) contoured at ±4σ. (d) Fo-Fc omit map of the allosteric binding site with the view rotated ~75° along the vertical axis from (b) contoured at ±4σ.

Supplementary Figure 5 The ion channel of the GlyRα3–glycine–AM-3607 complex in a desensitized state.

(a) Solvent contours of the transmembrane pore of the AM-3607 bound GlyRα3 pore showing the M2 helices of subunits A and C. Side chains of pore lining residues are shown. Numbering is according to the protein sequence and position in the M2 helix. Small purple, green and red spheres define a radius of >3.3 Å, 1.8-3.3 Å and <1.8 Å, respectively. (b), Contours of the glycine–ivermectin bound GlyRα1 pore, similar to panel (a). (c) Plot of pore radii as a function of distance along the pore axis for AM-3607 bound GlyRα3, glycine–ivermectin bound GlyRα1, ivermectin-bound GluClα, and benzamidine-bound GABAAR-β3. (d) Electrophysiological response to 30 μM glycine applied to HEK293T cells expressing human GlyRα3. Black (control) and blue (wash) traces are glycine application alone before and after co-application with 0.2 μM AM-3607 (red trace), showing potentiation of the glycine-induced current. (e) Desensitization of GlyRα3 upon stimulation with 1 mM glycine is not affected by subsequent co-application of 0.2 μM AM-3607.

Supplementary Figure 6 Putative sites of Cl– and Zn2+.

(a) The putative Cl- site with Cl- shown as green sphere and the side chains of Ala254 and Thr258 shown in sticks. The Fo-Fc omit map is contoured at 5σ. Subunit B has been removed for clarity. Distances from side chain carbons to Cl- are 5.4 – 6.4 Å. (b) The putative binding site of Zn2+ with Zn2+ shown as grey sphere and the side chains of Glu192, Asp194, and His215 shown as sticks. The NCS-averaged anomalous difference map is contoured at 5σ. Distances from Zn2+ to side chain oxygen atoms average 2.2 Å and to His215 nitrogen atoms average 2.6 Å across all five subunits.

Supplementary Figure 7 Binding of glycine to GlyRα3cryst without and with bound AM-3607.

(a) Determination of glycine affinity to apo GlyRα3cryst measured by SPR. KD value is mean ± s.e.m., determined from N=2 experiments. (b) Determination of glcyine affinity to AM-3607 bound GlyRα3cryst by ITC. Orthosteric ligand glycine was titrated into purified GlyRα3cryst preincubated with AM-3607. A representative titration is shown with non-linear best fit. Binding parameters were determined from N=2 experiments and are means ± s.d..

Supplementary Figure 8 Sequence alignment of GlyRα3cryst with representative eukaryotic Cys-loop-receptor family members.

Residue conservation is indicated by grey and black highlights. Residues involved in binding of AM-3607 are indicated by pale green (the principal subunit) and cyan (the complementary subunit) dots. Residues involved in binding of glycine are indicated by pale green (the principal subunit) and cyan (the complementary subunit) squares. Secondary structure elements are denoted by cylinders (helices) and arrows (strands) above the alignment. The alignment was generated using ClustalW. Protein sequences are from the following entires: Zebrafish GlyRα1 (PDB 3JAF), Human GlyRβ (Uniprot P48167), GluClcryst (PDB 4TNV), GABAAR-β3cryst (PDB 4COF), 5HT3A (PDB 4PIR), and T. marmorata nAchRα (Uniprot P02711).

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Huang, X., Shaffer, P., Ayube, S. et al. Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators. Nat Struct Mol Biol 24, 108–113 (2017). https://doi.org/10.1038/nsmb.3329

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