Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors

Abstract

The orexin (also known as hypocretin) G protein–coupled receptors (GPCRs) regulate sleep and other behavioral functions in mammals, and are therapeutic targets for sleep and wake disorders. The human receptors hOX1R and hOX2R, which are 64% identical in sequence, have overlapping but distinct physiological functions and potential therapeutic profiles. We determined structures of hOX1R bound to the OX1R-selective antagonist SB-674042 and the dual antagonist suvorexant at 2.8-Å and 2.75-Å resolution, respectively, and used molecular modeling to illuminate mechanisms of antagonist subtype selectivity between hOX1R and hOX2R. The hOX1R structures also reveal a conserved amphipathic α-helix, in the extracellular N-terminal region, that interacts with orexin-A and is essential for high-potency neuropeptide activation at both receptors. The orexin-receptor crystal structures are valuable tools for the design and development of selective orexin-receptor antagonists and agonists.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structures of hOX1R bound to suvorexant and SB-674042.
Figure 2: Computational modeling of SB-674042 binding.
Figure 3: Binding of antagonists to hOX2R subtype-swap mutants.
Figure 4: Computational modeling of 2-SORA-DMP binding.
Figure 5: Function of the orexin-receptor N terminus.

Accession codes

Primary accessions

Protein Data Bank

Referenced accessions

Protein Data Bank

References

  1. Marcus, J.N. et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6–25 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Li, J., Hu, Z. & de Lecea, L. The hypocretins/orexins: integrators of multiple physiological functions. Br. J. Pharmacol. 171, 332–350 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. de Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. USA 95, 322–327 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lin, L. et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Chemelli, R.M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Willie, J.T. et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron 38, 715–730 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Zheng, H., Patterson, L.M. & Berthoud, H.-R. Orexin signaling in the ventral tegmental area is required for high-fat appetite induced by opioid stimulation of the nucleus accumbens. J. Neurosci. 27, 11075–11082 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Harris, G.C., Wimmer, M. & Aston-Jones, G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437, 556–559 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Boutrel, B. et al. Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc. Natl. Acad. Sci. USA 102, 19168–19173 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bingham, S. et al. Orexin-A, an hypothalamic peptide with analgesic properties. Pain 92, 81–90 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Johnson, P.L. et al. A key role for orexin in panic anxiety. Nat. Med. 16, 111–115 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Winrow, C.J. & Renger, J.J. Discovery and development of orexin receptor antagonists as therapeutics for insomnia. Br. J. Pharmacol. 171, 283–293 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Funato, H. et al. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab. 9, 64–76 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xie, X. et al. Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia. J. Clin. Invest. 118, 2471–2481 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Aston-Jones, G., Smith, R.J., Moorman, D.E. & Richardson, K.A. Role of lateral hypothalamic orexin neurons in reward processing and addiction. Neuropharmacology 56 (suppl. 1), 112–121 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Cui, J.J. et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J. Med. Chem. 54, 6342–6363 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Rosenbaum, D.M. et al. GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science 318, 1266–1273 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Caffrey, M. Crystallizing membrane proteins for structure determination: use of lipidic mesophases. Annu. Rev. Biophys. 38, 29–51 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. White, J.F. et al. Structure of the agonist-bound neurotensin receptor. Nature 490, 508–513 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yin, J., Mobarec, J.C., Kolb, P. & Rosenbaum, D.M. Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. Nature 519, 247–250 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Cox, C.D. et al. Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J. Med. Chem. 53, 5320–5332 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Caffrey, M. & Cherezov, V. Crystallizing membrane proteins using lipidic mesophases. Nat. Protoc. 4, 706–731 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Palczewski, K. et al. Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289, 739–745 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Hanson, M.A. et al. Crystal structure of a lipid G protein-coupled receptor. Science 335, 851–855 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cox, C.D. et al. Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding. Bioorg. Med. Chem. Lett. 19, 2997–3001 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Langmead, C.J. et al. Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br. J. Pharmacol. 141, 340–346 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Tran, D.-T. et al. Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists. Eur. J. Pharmacol. 667, 120–128 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Putula, J. & Kukkonen, J.P. Mapping of the binding sites for the OX1 orexin receptor antagonist, SB-334867, using orexin/hypocretin receptor chimaeras. Neurosci. Lett. 506, 111–115 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Heifetz, A. et al. Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site-directed mutagenesis. Biochemistry 51, 3178–3197 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Malherbe, P. et al. Mapping the binding pocket of dual antagonist almorexant to human orexin 1 and orexin 2 receptors: comparison with the selective OX1 antagonist SB-674042 and the selective OX2 antagonist N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). Mol. Pharmacol. 78, 81–93 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Müller, C.E. & Jacobson, K.A. in Methylxanthines Vol. 200 (ed. Fredholm, B.B.) 151–199 (Springer, 2011).

  33. Huang, S.-Y. & Zou, X. Scoring and lessons learned with the CSAR benchmark using an improved iterative knowledge-based scoring function. J. Chem. Inf. Model. 51, 2097–2106 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li, Y., Han, L., Liu, Z. & Wang, R. Comparative assessment of scoring functions on an updated benchmark: 2. Evaluation methods and general results. J. Chem. Inf. Model. 54, 1717–1736 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Friesner, R.A. et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem. 49, 6177–6196 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Lyne, P.D., Lamb, M.L. & Saeh, J.C. Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. J. Med. Chem. 49, 4805–4808 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Kim, H.-Y., Hong, E., Kim, J.-I. & Lee, W. Solution structure of human orexin-A: regulator of appetite and wakefulness. J. Biochem. Mol. Biol. 37, 565–573 (2004).

    CAS  PubMed  Google Scholar 

  38. Lee, J.H. et al. Solution structure of a new hypothalamic neuropeptide, human hypocretin-2/orexin-B. Eur. J. Biochem. 266, 831–839 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Isberg, V. et al. GPCRDB: an information system for G protein-coupled receptors. Nucleic Acids Res. 42, D422–D425 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Rosenbaum, D.M. et al. Structure and function of an irreversible agonist-β2 adrenoceptor complex. Nature 469, 236–240 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Katritch, V., Cherezov, V. & Stevens, R.C. Structure-function of the G protein-coupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol. 53, 531–556 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Ye, N., Neumeyer, J.L., Baldessarini, R.J., Zhen, X. & Zhang, A. Update 1 of: recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders. Chem. Rev. 113, PR123–PR178 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Granier, S. et al. Structure of the δ-opioid receptor bound to naltrindole. Nature 485, 400–404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. German, N.A., Decker, A.M., Gilmour, B.P., Thomas, B.F. & Zhang, Y. Truncated orexin peptides: structure-activity relationship studies. ACS Med. Chem. Lett. 4, 1224–1227 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kufareva, I. et al. Stoichiometry and geometry of the CXC chemokine receptor 4 complex with CXC ligand 12: molecular modeling and experimental validation. Proc. Natl. Acad. Sci. USA 111, E5363–E5372 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ahmed, S.S. et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci. Transl. Med. 7, 294ra105 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Zhao, H., Piszczek, G. & Schuck, P. SEDPHAT: a platform for global ITC analysis and global multi-method analysis of molecular interactions. Methods 76, 137–148 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Kobilka, B.K. Amino and carboxyl terminal modifications to facilitate the production and purification of a G protein-coupled receptor. Anal. Biochem. 231, 269–271 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Horcajada, C., Guinovart, J.J., Fita, I. & Ferrer, J.C. Crystal structure of an archaeal glycogen synthase: insights into oligomerization and substrate binding of eukaryotic glycogen synthases. J. Biol. Chem. 281, 2923–2931 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Karplus, P.A. & Diederichs, K. Linking crystallographic model and data quality. Science 336, 1030–1033 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data. Methods Enzymol. 276, 307–326 (1997).

    CAS  PubMed  Google Scholar 

  52. McCoy, A.J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Adams, P.D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cowtan, K. Fitting molecular fragments into electron density. Acta Crystallogr. D Biol. Crystallogr. 64, 83–89 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Painter, J. & Merritt, E.A. TLSMD web server for the generation of multi-group TLS models. J. Appl. Crystallogr. 39, 109–111 (2006).

    Article  CAS  Google Scholar 

  57. Schüttelkopf, A.W. & van Aalten, D.M.F. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D Biol. Crystallogr. 60, 1355–1363 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Chen, V.B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 (2010).

    CAS  PubMed  Google Scholar 

  59. Sastry, G.M., Adzhigirey, M., Day, T., Annabhimoju, R. & Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des. 27, 221–234 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Jakubík, J., El-Fakahany, E.E. & Doležal, V. Towards predictive docking at aminergic G-protein coupled receptors. J. Mol. Model. 21, 284 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Bowers, K.J., Chow, E., Xu, H. & Dror, R.O. Scalable algorithms for molecular dynamics simulations on commodity clusters. Proc. 2006 ACM/IEEE Conf. Supercomputing (IEEE, 2006).

  62. Shrake, A. & Rupley, J.A. Environment and exposure to solvent of protein atoms. Lysozyme and insulin. J. Mol. Biol. 79, 351–371 (1973).

    Article  CAS  PubMed  Google Scholar 

  63. Friesner, R.A. et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem. 47, 1739–1749 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Hojayev, B., Rothermel, B.A., Gillette, T.G. & Hill, J.A. FHL2 binds calcineurin and represses pathological cardiac growth. Mol. Cell. Biol. 32, 4025–4034 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Keller, S. et al. High-precision isothermal titration calorimetry with automated peak-shape analysis. Anal. Chem. 84, 5066–5073 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge support from the Welch Foundation (I-1770 to D.M.R.), the Searle Scholars Program (D.M.R.) and a Packard Foundation Fellowship (D.M.R.). The National Institute of General Medical Sciences and National Cancer Institute Structural Biology Facility at the Advanced Photon Source (GM/CA@APS) is funded in whole or in part with Federal funds from the US National Institutes of Health, National Cancer Institute (ACB-12002) and National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. We thank B. Rothermel, L. Lum and L. Zhang (University of Texas Southwestern Medical Center) for materials and assistance with the NFAT-luciferase assay, and S. Lee (University of Texas Southwestern Medical Center) for help with immunofluorescence.

Author information

Authors and Affiliations

Authors

Contributions

J.Y. expressed, purified and crystallized the hOX1R-PGS fusion protein, collected diffraction data, solved the structures, carried out ITC experiments and performed NFAT-luciferase assays. K.B. carried out computational docking and simulation experiments for orexin-receptor antagonists. C.A.B. and T.H.S. supervised, designed and analyzed ITC experiments. L.C. and Z.S. assisted with expression and purification of the hOX1R-PGS fusion protein. C.M.H. performed and analyzed radioligand binding assays to measure orexin receptor–ligand affinities. A.J.R. designed and synthesized 2-SORA-DMP. A.L.G., C.J.W., J.J.R. and P.J.C. analyzed docking and simulation experiments for orexin-receptor antagonists and devised experiments to measure receptor function. D.M.R. supervised the overall project, assisted with collection of diffraction data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Daniel M Rosenbaum.

Ethics declarations

Competing interests

K.B., C.M.H., A.L.G., A.J.R., C.J.W., J.J.R. and P.J.C. are employees of Merck & Co., receive salary and research support from the company and may own stock and/or stock options in the company.

Integrated supplementary information

Supplementary Figure 1 Purification and crystallization of hOX1R-PGS.

(a) Superdex 200 size exclusion profiles of suvorexant-bound hOX1R-PGS (black) and SB-674042-bound hOX1R-PGS (purple).

(b) Coomassie stained PAGE gel of the isolated peak fractions from size exclusion chromatography. Left of markers: SB-674042-bound hOX1R-PGS; Right of markers: suvorexant-bound hOX1R-PGS.

(c) Lipidic cubic phase (LCP) crystallization setup for suvorexant-bound hOX1R-PGS

(d) Equivalent LCP setup for SB-674042-bound hOX1R-PGS.

Supplementary Figure 2 Electron density maps for hOX1R structures.

(a) Stereo view of 2Fo-Fc map, contoured at 1.5 σ, for the region of suvorexant-bound hOX1R containing the ligand, TM2, and TM5.

(b) Stereo view of 2Fo-Fc map, contoured at 1.5 σ, for the equivalent region of the SB-674042-bound hOX1R structure.

Supplementary Figure 3 Electron density and contact maps for the OXR binding pockets.

(a) Stereo view of 2Fo-Fc map, contoured at 1.5 σ, for the residues within 4 Å contact of the ligand in the hOX1R structure bound to SB-674042. Receptor is in blue sticks, ligand is in magenta. At right is a contact map for the antagonist made using LIGPLOT (Wallace, A. et al., Protein Eng. 8, 127-134, 1995).

Average B-factor for contact residues = 41.4 Å2, average B-factor for receptor = 52.8 Å2.

(b) Same as in (a), except for hOX1R (blue) bound to suvorexant (yellow).

Average B-factor for contact residues = 40.9 Å2, average B-factor for receptor = 51.8 Å2.

(c) Same as in (a), except for hOX2R (orange) bound to suvorexant (yellow), pdb 4S0V (Yin, J. et al., Nature 519, 247-250, 2015).

Average B-factor for contact residues = 30.5 Å2, average B-factor for receptor = 41.2 Å2.

Supplementary Figure 4 Molecular dynamics (MD) simulations of suvorexant in hOX1R and hOX2R.

(a) MD simulation trajectory for suvorexant-bound hOX1R. RMSD versus Time is shown for the Cα protein backbone (blue) and the ligand heavy atoms (magenta).

(b) Same as in a, except for suvorexant-bound hOX2R.

Supplementary Figure 5 Binding of 2-SORA-DMP to the orexin receptors.

Radioligand competition assays for 2-SORA-DMP binding to hOX1R (left) or hOX2R (right) membranes. For both panels, n = 3, replicates are from three separate competition assays on the same cell membrane stock. Error bars represent ± s.e.m.

Supplementary Figure 6 Sequence alignment of orexin-receptor N termini.

Alignment includes OX1R and OX2R sequences from Mus musculus (mouse), human, Bos taurus (bovine), Danio rerio (fish), Xenopus laevis (frog), and Canis lupus (dog). The magenta sequences comprise the N-terminal region that is ordered in the hOX1R structures. Sequences were downloaded from the GPCRDB (http://www.gpcr.org/7tm), and alignment was carried out with ClustalW2 (http://www.ebi.ac.uk/Tools/msa/clustalw2).

Supplementary Figure 7 Cell-surface immunofluorescence staining of orexin-receptor constructs.

Images for transfected CHO-K1 cell surface staining with Alexa488-conjugated M1-anti-FLAG antibody (Sigma) for different orexin receptor constructs (as in Rosenbaum, D.M. et al., Science 318, 1266-1273, 2007). Three separate fields from the same pool of stained cells are shown for each construct.

Supplementary Figure 8 Functional comparison of hOX1R I319 and hOX1R V319.

(a) Dose-response to orexin-A in CHO-K1 cell NFAT-luciferase activation assay. For a and b, n = 3, replicates are from three separate assays on the same transfected cells. Error bars represent ± s.d.

(b) Inhibition of orexin-A (20 nM) signal propagation by increasing concentrations of the antagonist SB-674042.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Table 1 (PDF 1643 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yin, J., Babaoglu, K., Brautigam, C. et al. Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. Nat Struct Mol Biol 23, 293–299 (2016). https://doi.org/10.1038/nsmb.3183

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.3183

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research