High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist


Parathyroid hormone 1 receptor (PTH1R) is a class B multidomain G-protein-coupled receptor (GPCR) that controls calcium homeostasis. Two endogenous peptide ligands, parathyroid hormone (PTH) and parathyroid hormone–related protein (PTHrP), activate the receptor, and their analogs teriparatide and abaloparatide are used in the clinic to increase bone formation as an effective yet costly treatment for osteoporosis. Activation of PTH1R involves binding of the peptide ligand to the receptor extracellular domain (ECD) and transmembrane domain (TMD), a hallmark of class B GPCRs. Here, we present the crystal structure of human PTH1R in complex with a peptide agonist at 2.5-Å resolution, allowing us to delineate the agonist binding mode for this receptor and revealing molecular details within conserved structural motifs that are critical for class B receptor function. Thus, this study provides structural insight into the function of PTH1R and extends our understanding of this therapeutically important class of GPCRs.

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Fig. 1: PTH1R–ePTH complex crystal structure.
Fig. 2: Structural and functional details of PTH1R–ePTH interactions.
Fig. 3: Water-mediated extension and conformational changes upon activation in the central polar network.
Fig. 4: Influence of bulky residues in helices I and II on the activation of class B GPCRs.

Data availability

Coordinates and structure factors have been deposited in Protein Data Bank (PDB 6FJ3). All other data are available from the corresponding authors upon reasonable request.


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We thank B. Blattmann of the Protein Crystallisation Center at the University of Zurich for his support with crystallization, the staff of the X06SA beamline at the Paul Scherrer Institute for support during data collection and I. Berger at the European Molecular Biology Laboratory for providing us with baculovirus transfer vectors. We also thank G. Meier and B. Aebli for support during protein production. This work was supported by Schweizerischer Nationalfonds Grants 31003A_153143 and 31003A_182334 and KTI grant 18022.1 PFLS-LS, all to A.P.; C.K. is the recipient of a fellowship of the German Academy of Sciences Leopoldina (LPDS 2009-48) and a Marie Curie fellowship of the European Commission (FP7-PEOPLE-2011-IEF #299208).

Author information

C.K., with the help of L.K., performed directed evolution in yeast. J.E. and J.S. carried out the rational mutagenesis for further thermostabilization of the receptor. J.E., J.S. and C.K. characterized expression constructs and optimized protein expression. J.E. and J.S. designed and characterized crystallization constructs; expressed, purified and crystallized PTH1R; and harvested crystals. J.E., J.S. and A.S.D. collected diffraction data. J.E., J.S., M.R. and A.S.D. processed the data and solved and refined the structure. C.K. performed pharmacological characterization. C.K. and A.P. designed the project. Project management was carried out by J.E., J.S., C.K. and A.P. The manuscript was prepared by J.E., J.S., C.K. and A.P. All authors contributed to the final editing and approval of the manuscript.

Correspondence to Christoph Klenk or Andreas Plückthun.

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Competing interests

M.R., L.K. and A.S.D. are employees of Heptares Therapeutics, a company with activities in the GPCR field.

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Integrated supplementary information

Supplementary Figure 1 Overview of the crystallized PTH1R construct and thermostability of PTH1R mutant TMDs.

a, Snake plot of the crystallized ECD-PTH1RS-PGS (PTH1RXTAL) construct. The native signal peptide of PTH1R (residues 1–23) was replaced by a melittin signal peptide (dashed circles), followed by a FLAG epitope (red), a His10 tag (purple) and a 3C protease cleavage site (orange). Residues 61–104 within the ECD and 481–593 at the receptor C terminus were deleted. Residues 389–397 of ICL3 were replaced by a PGS fusion. Mutations from directed evolution in S. cerevisiae and the additionally introduced stabilizing mutations are highlighted in green and blue, respectively. Disulfide bonds are indicated as yellow lines. Glycosylation sites observed in the crystal structure are indicated by a trident. The first and last residues of helices I to VIII are labeled with the residue number. Residues that are not resolved in the crystal structure are shown in gray. b, Thermostability assay (CPM) of the TMD of the yeast-evolved PTH1R (PTH1R-SaBRE), the further thermostabilized PTH1R (PTH1RS) and the PTH1RS-PGS fusion (PTH1RS-PGS) bound to [Ac5c1, Aib3, Q10, Hrg11, A12, W14]PTH(1–14) (respective melting temperatures are 53.0 °C, 57.6 °C and 60.9 °C).

Supplementary Figure 2 Comparison of PTH peptide sequences and in vitro pharmacology of ligands and receptor constructs.

a, Sequence alignment of human PTH (wt PTH) and engineered ePTH. Colored boxes depict sequence changes in comparison to wt PTH, and black boxes denote non-natural amino acids. The topology of PTH1R interaction is indicated on top. Ac5c, aminocyclopentane-1-carboxylic acid; Aib, α-aminoisobutyric acid; Hrg, homoarginine; Nle, norleucine. b, Thermostability assay (CPM) of the crystallized ECD-PTH1RS-PGS (PTH1RXTAL) fusion bound to wt PTH(1–34), wt PTHrP(1–36) and ePTH (respective melting temperatures are 58.0 °C, 58.4 °C and 65.0 °C). Data shown are from a representative experiment. c, Binding of PTH-HL647 to HEK293T cells expressing wt PTH1R in the presence of different concentrations of unlabeled PTH peptides. d, cAMP accumulation measured in HEK293T cells expressing wt PTH1R. e, IP1 accumulation measured in HEK293T cells expressing wt PTH1R. f,g, Binding of PTH-HL647 to HEK293T cells expressing wt PTH1R or the crystallized PTH1R with the PGS fusion (PTH1RXTAL) in the presence of different concentrations of unlabeled ePTH (f) or wt PTH(1–34) (g). h, cAMP accumulation measured in HEK293T cells expressing wt PTH1R or the crystallized PTH1R with the PGS fusion (PTH1RXTAL). Data shown in ch are mean values ± s.e.m. from five (c,f,g), four (d,e) or three (h) independent experiments performed in duplicate. The IC50 values for c, f and g are listed in Supplementary Table 2.

Supplementary Figure 3 PTH1R crystallization.

a, Bright-field image of PTH1R crystals in lipidic cubic phase. b, SDS–PAGE gel of purified PTH1RXTAL (upper band with molecular mass 68.3 kDa) bound to ePTH (lower band with molecular mass 4.3 kDa). c, Size-exclusion profile of PTH1RXTAL-ePTH complex on a Nanofilm SEC-250 column (Sepax Technologies). df, Crystal packing with unit cell indicated in black, axes indicated by arrows (green, TMD; purple, ECD; blue, PGS; orange, ePTH). d, View along a axis. e, View along b axis. f, View along c axis. g, B factor putty of PTH1R (blue, low B factors; red, high B factors). Relatively high B factors are observed within the ECLs and the linker connecting ECD and TMD.

Supplementary Figure 4 Atomic model of the PTH1R-ePTH complex in the electron density map.

ac, The 2Fo – Fc electron density map contoured at 1.0σ and model are shown for all seven transmembrane helices, helix VIII and ePTH (a,b) and the PTH1R-ePTH interacting residues (c). Boxes i–iv illustrate the specific regions of ligand interaction with the receptor.

Supplementary Figure 5 Comparison of the structures of wt PTH and ePTH bound to PTH1R and the role of glycosylation at N161 on PTH binding.

a, Overlay of the crystal structures of the ECDs of PTH1R-ePTH (purple and orange) and of the isolated ECD in complex with wt PTH(1–34) (PDB 3C4M, gray) with ligand residues shown in stick representation. Residues in ePTH differing from wt PTH are highlighted in green. b, Superposition of ePTH with the crystal structure of wt PTH(1–34) (PDB 1ET1, gray). c, ePTH with the FoFc omit density map contoured at 2.5σ. d, ECD of PTH1R with glycosylation (gray) resolved at residue N161 in close proximity to ePTH (orange) shown in sticks. The hydrogen bonds (dashed blue lines) between the amidated peptide C terminus of Y34 and T163 of PTH1R rationalize the reported increase in binding affinity of C-terminal amides over carboxylic acids in PTH(1–34) peptides (Proceedings of the Fifth Parathyroid Conf. 33–39, 1975). The 2Fo – Fc electron density in gray mesh is contoured at 1.0σ. e, Binding of PTH-HL647 to HEK293T cells expressing wt PTH1R and the mutant PTH1R_N161D in the presence of different concentrations of unlabeled PTH peptide. Data are shown as mean values ± s.e.m. from n = 7 independent experiments performed in duplicate. The IC50 values for wt and PTH1R_N161D are listed in Supplementary Table 2.

Supplementary Figure 6 Conserved residues and implication of R440 in ligand binding and receptor activation.

a, Extracellular view on the conserved tryptophan in ECL2 of superposed structures of PTH1R-ePTH (green-orange), GCGR-NNC1702 (yellow; PDB 5YQZ), GLP1R-ExP5 (blue; PDB 6B3J) and GLP1R-GLP1 (gray; PDB 5VAI) complexes. While this tryptophan is positioned between transmembrane helices III and IV in the structures of the other peptide-bound class B GPCRs, it is found in a different orientation packed against the ligand in the PTH1R-ePTH complex. b, The distinct orientation of W352 in PTH1R is defined by the clear side chain electron density in the 2Fo – Fc map contoured at 1.0σ. c, The stabilizing mutation R4407.38 (Q4407.38 in wt PTH1R) forms a hydrogen bonding network to ePTH via E4447.42 and to the backbone oxygen of F4246.56 at the extracellular end of helix VI. d, Binding of PTH-HL647 to HEK293T cells expressing wt or mutated PTH1R in the presence of different concentrations of unlabeled PTH peptides. Mutation of Q4407.38 to arginine largely retains ligand binding, whereas disruption of the hydrogen bond to E4447.42 by introduction of small, apolar side chain residues severely reduces ligand binding (Mol. Endocrinol. 9, 1269–1278, 1995). e,f, Normalized concentration–response curves for cAMP (e) or IP1 (f) accumulation, measured in HEK293T cells expressing wt or mutant PTH1R. In contrast to Q4407.38 of wt PTH1R, the extended sidechain of R4407.38 stabilizes the top of helix VI by an additional hydrogen bond to F4246.56 and thus strongly reduces receptor activation, which requires conformational rearrangements at the extracellular end of helix VI. g, Amino acid alignment of specific conserved residues of 15 human class B GCPRs grouped into those of the central polar network, those involved in receptor activation, the P-x-x-G motif and in the orthosteric binding pocket (Wootten numbering is given as a superscript). Data in d and e are shown as mean values ± s.e.m. from seven (d), five (e) or three (f) independent experiments performed in duplicate. The IC50 values of d are listed in Supplementary Table 2.

Supplementary Figure 7 Binding of PTH(1–34) to wild-type and mutant variants of PTH1R.

Binding of PTH-HL647 to HEK293T cells expressing wild-type and mutated PTH1R variants in the presence of different concentrations of unlabeled wt PTH(1–34) as a competitor. Data are shown as mean values ± s.e.m. from 4–12 independent experiments performed in duplicate. The corresponding IC50 values and numbers of independent experiments for wt and mutant PTH1Rs are listed in Supplementary Table 2.

Supplementary Figure 8 Jansen’s metaphyseal chondrodysplasia–related mutations at the conserved HETX motif result in constitutive PTH1R activation.

a, Extracellular view on the class B conserved HETX motif of superposed PTH1R (green) and activated GLP1R (blue; PDB 5VAI). In the active state receptor, T6.42 is removed from the network owing to rearrangements in transmembrane helix VI. Residues associated with Jansen’s metaphyseal chondrodysplasia are highlighted in red. b,c, The thermostabilizing mutation I4587.56A in the crystallized PTH1R and the Jansen’s Metaphyseal Chondrodysplasia-related mutation I4587.56R facing towards S4096.41 are located close to the HETX motif (view from the membrane). The bulky side chain of I4587.56R clashes (indicated by red disks) with helix VI in the inactive receptor state (representative rotamer from PyMOL Mutagenesis Wizard shown).

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Ehrenmann, J., Schöppe, J., Klenk, C. et al. High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist. Nat Struct Mol Biol 25, 1086–1092 (2018). https://doi.org/10.1038/s41594-018-0151-4

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