Abstract
The angiotensin II receptors AT1R and AT2R serve as key components of the renin–angiotensin–aldosterone system. AT1R has a central role in the regulation of blood pressure, but the function of AT2R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT2R bound to an AT2R-selective ligand and to an AT1R/AT2R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure–activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.
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Acknowledgements
This work was supported by the National Institutes of Health (NIH) grants R01 GM108635 (V.C.) and U54 GM094618 (V.K., V.C. and R.C.S.); the National Science Foundation (NSF) grant 1231306 (U.W. and W.L.); the Helmholtz Association through program oriented funds (T.A.W. and A.T.). A.T. acknowledges financial support from ‘X-probe’ funded by the European Union’s 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement 637295. Parts of this research were carried out at the Coherent X-ray Imaging (CXI) end station of the Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, operated by Stanford University on behalf of the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515, and at the GM/CA CAT and IMCA-CAT of the Advanced Photon Source, Argonne National Laboratory. Parts of the sample delivery system used at LCLS for this research was funded by the NIH grant P41GM103393. Computational part of the study was supported by the University of Southern California Center for High-Performance Computing and Communications (https://hpcc.usc.edu/). We thank J. Velasquez for help with molecular biology, M. Chu for help with baculovirus expression, M. Hanson for help with crystallographic data processing and A. Walker for assistance with manuscript preparation.
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K.H., S.M.S., R.C.S., V.K. and V.C. conceived and managed the project. H.Z. designed, optimized, purified, and characterized receptor constructs for structural studies, crystallized the receptor in LCP. H.Z. and A.I. collected and processed synchrotron data. H.Z., A.B., A.I., M.S.H., U.W., W.L. and V.C. collected XFEL data. A.B., A.T. and T.A.W. processed XFEL data. G.W.H., H.Z. and A.B. solved and refined the structures. M.T.R., K.H., K.B., E.L.M., S.M.S. and S.S. interpreted the structure and designed experiments. R.D.K. and J.M.S. prepared VLPs for binding studies. P.S., M.G.-C. and B.Z. designed the binding experiments. B.Z. carried out radioligand-binding assays with VLPs. H.Z., B.Z., M.G.-C., A.S., N.P. and P.S. analysed the data and compiled the figures for the manuscript. N.P., A.S. and V.K. performed docking and molecular dynamics simulations. K.L.W. performed radioligand-binding experiments with receptor mutants. M.T.R., K.H. and K.B. selected compounds for SAR study and interpreted the data. H.Z., V.K. and V.C. wrote the manuscript with contributions from M.T.R. and K.H.
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B.Z., M.T.R., K.H., K.B., E.L.M., S.M.S., R.D.K., J.M.S., S.S., M.G.-C. and P.S. are employees of Merck & Co., Inc., Kenilworth, New Jersey, USA, receive salary and research support from the company and may own stock and/or stock options in the company. Other authors declare no competing financial interests.
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Extended data figures and tables
Extended Data Figure 1 AT2R ‘snake’ diagram and protein engineering.
Truncations are shown in grey, disulfide bonds in yellow, ligand-binding residues in red, and conserved motifs in green.
Extended Data Figure 2 Radioligand-binding assays.
a, b, Saturation binding of compound 1 and Sar1-Ile8-angiotensin II. Specific binding of [3H]compound 1 (a) and [125I]Sar1-Ile8-angiotensin II (b) to the wild-type (open circle) and engineered (closed triangle) AT2R, representative of two separate experiments. c–e, Competition binding of compound 1 (open circle), compound 2 (closed triangle) and angiotensin II (open square) to the wild-type AT2R (c), engineered AT2R (d) and wild-type AT1R (e) with [125I]Sar1-Ile8-angiotensin II as a tracer; each point represents the mean ± s.d. of two separate experiments, performed in duplicate.
Extended Data Figure 3 Crystallization of AT2R and crystal packing.
a, AT2R–compound 1 crystals grown in a syringe for XFEL data collection. b, AT2R–compound 2 crystals grown in a glass sandwich plate for synchrotron data collection. c, Crystal packing in the monoclinic space group (AT2R–compound 1 and AT2R–compound 2 structures), side and top views (AT2R in green and cyan; BRIL in orange and pink). d, Crystal packing in the orthorhombic space group (AT2R–compound 1 structure), side and top views (AT2R in cyan; BRIL in blue). e, Different BRIL orientations in the two BRIL–AT2R molecules in the asymmetric unit of monoclinic AT2R–compound 1 structure and AT2R–compound 2 structure (pink and orange), and in the orthorhombic AT2R–compound 1 structure (blue) with AT2R in cyan, side and top views. Unit cell in c and d is outlined by the black line.
Extended Data Figure 4 Conserved L[M]3.46-I[A]6.37-Y[Y]7.53 microswitch and sodium-binding pocket in AT1R and AT2R.
a, Comparison of the conserved residue triad between the AT1R (green, PDB code 4YAY) and AT2R (cyan) structures shows a rearrangement of interactions consistent with AT2R activation. b, Modelling of the AT2R in a hypothetical inactive state (cyan) based on the AT1R crystal structure template (green) shows that replacement of a large hydrophobic residue in position 6.37, which is conserved in most class A GPCRs, to a rare small Ala2586.37 in AT2R markedly reduces the hydrophobic contact in this region between helices III and VI in the inactive state. c, d, Sodium-binding pocket in AT2R (c) and AT1R (PDB code 4YAY) (d) is shown as a surface with hydrogen bonds between Asn7.46 and Asn3.35 as orange spheres. Putative sodium ion in the AT1R structure (d) is shown as a solid magenta sphere, while the same position in the AT2R structure (c) is marked as a dotted sphere. Potential sodium-coordinating residues are shown as sticks.
Extended Data Figure 5 Summary of molecular dynamics simulations.
a–c, Conformational stability of the AT2R structure is illustrated by representative conformations (c) from a total of 4 μs of molecular dynamics simulations (8 independent 500 ns runs), clustered by r.m.s.d. Traces of distances measured between different helices are shown for apo AT2R (a) and for the AT2R–compound 1 complex (b). Distances were calculated between the centres of mass of residues Ser792.39-Ile832.43 for helix II, Arg1423.50-Val1463.54 for helix III, Gln2536.32-Met2576.36 for helix VI, and Phe325-Lys328 for helix VIII. d, e, Conformational stability of helix VIII upon perturbations, using eight starting conformations of helix VIII (d) is revealed by r.m.s.d. traces (e), which all converge by ~250 ns of simulations. r.m.s.d. values are calculated for the centre of mass of Cα atoms of residues Phe325-Lys328 compared to the crystal structure of AT2R. Tick marks on the y axis show the starting frame r.m.s.d. values. Coloured lines are plotted using values averaged over a 500 ps window. f–h, Results of molecular dynamics simulations for a modified AT2R model with the backbone of helix VIII aligned with helix VIII from AT1R structure (PDB code 4YAY). Conformational snapshots of the AT2R model (f) are shown for every 100 ns (blue to red spectrum) from one of the six independent 700 ns molecular dynamics simulation runs (simulation 5). Green cartoon shows inactive-state conformation of CCR5 (PDB code 4MBS), helix VIII of which was found to be the closest to the final conformations of AT2R helix VIII in molecular dynamics simulations. Intracellular view (g) of snapshots from the same molecular dynamics simulation is shown, but at t = 0 and t = 700 ns. Traces of the distance between helices VI and II (h, top curves), calculated between the centres of mass of Cα atoms of residues Gln2536.32-Met2576.36 in helix VI and residues Ser792.39-Ile832.43 in helix II, show a change from 21 Å (active state) to under 16 Å (inactive state). Traces of the distance between helix VIII and the membrane (h, bottom curves), calculated between the centre of mass of Cα atoms of residues Arg330-Val332 and the closest phosphate atoms of lipid molecules, indicate a gradual shift of helix VIII towards the lipid bilayer, with the distance decreasing from ~10 Å to under 3 Å.
Extended Data Figure 6 Electron density for compounds 1 and 2.
a, b, Compound 1 can be modelled in two possible conformations (a and b), with alternative orientations of the benzene and thiophene rings. c, d, Compound 2 can be modelled in two possible conformations (c and d), with alternative orientations of the benzene and furan rings. 2mFo − DFc electron density (blue mesh) for compound 1 contoured at 1σ, and mFo − DFc density (green mesh: positive; red mesh: negative) contoured at 3σ. The conformations shown in a and c were used in the final crystal structures because of a slightly better ligand fit and the absence of strong difference mFo − DFc density. Both conformations for each ligand, however, are possible and indistinguishable by docking studies.
Extended Data Figure 7 Ligand binding and cross-docking in AT2R and AT1R structures.
a, b, Docking poses of compound 1 (magenta), compound 2 (yellow), olmesartan (blue) and ZD7155 (orange) in the crystal structures of AT2R (a) and AT1R (b). Receptors are shown in carton representation, ligands are shown as sticks, and hydrogen bonds/salt bridges are shown as dashed lines. c, Ligand binding affinities and docking scores for AT2R and AT1R ligands. Data for the cognate ligands are shown in bold. Inactive state AT1R and active-like state of AT2R correspond to crystal structures. Active-like state of AT1R and inactive state of AT2R were modelled based on the crystal structures of AT2R and AT1R, respectively.
Extended Data Figure 8 Mutagenesis of the AT2R ligand-binding pocket.
a, Ligand-binding pocket from the AT2R–compound 1 crystal structure. b, Ligand-binding pocket from the AT1R–olmesartan crystal structure. c, Schematics of interactions between compound 1 and AT2R residues. d, Schematics of interactions between olmesartan and AT1R residues. In all panels, residues are coloured according to their effect on affinity: more than 100-fold decrease in affinity (orange); 5–100-fold decrease in affinity (yellow); and less than 5-fold decrease in affinity (grey). e, Effects of single residue mutations in the AT2R ligand-binding pocket on the ligand binding affinities. Values represent mean ± s.d. with the number of experiments shown in parenthesis.
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Zhang, H., Han, G., Batyuk, A. et al. Structural basis for selectivity and diversity in angiotensin II receptors. Nature 544, 327–332 (2017). https://doi.org/10.1038/nature22035
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DOI: https://doi.org/10.1038/nature22035
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