CoChat
Sign Up
PreprintCited by 26Sphingolipid Metabolism and SignalingReceptor Mechanisms and SignalingProtein Kinase Regulation and GTPase Signaling

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Structural basis for receptor selectivity and inverse agonism in S1P 5 receptors

Open access
Lyapina, Elizaveta, Marin, Egor, Gusach, Anastasiia, Orekhov, Philipp, Gerasimov, Andrey, Luginina, Aleksandra, Vakhrameev, Daniil, Ergasheva, Margarita, Kovaleva, Margarita, Khusainov, Georgii, Khorn, Polina, Shevtsov, Mikhail, Kovalev, Kirill, Okhrimenko, Ivan, Popov, Petr, Hu, Hao, Weierstall, Uwe, Liu, Wei, Cho, Yunje, Gushchin, Ivan, Rogachev, Andrey, Bourenkov, Gleb, Park, Sehan, Park, Gisu, Hyun, Hyo Jung, Park, Jaehyun, Gordeliy, Valentin, Borshchevskiy, Valentin, Mishin, Alexey, Cherezov, Vadim·2022·Nature Communications
DOI 10.1101/2022.02.25.480536PMC PMC9374744

Preprint — published as 10.1038/s41467-022-32447-1 · Paper page

Open this paper in CoChat — free accountOpen PDF

Abstract

The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PR) - S1P 1-5 . S1P 5 is predominantly expressed in nervous and immune systems, regulating the egress of natural killer cells from lymph nodes and playing a role in immune and neurodegenerative disorders, as well as carcinogenesis. Several S1PR therapeutic drugs have been developed to treat these diseases; however, they lack receptor subtype selectivity, which leads to side effects. In this article, we describe a 2.2 Å resolution room temperature crystal structure of the human S1P 5 receptor in complex with a selective inverse agonist determined by serial femtosecond crystallography (SFX) at the Pohang Accelerator Laboratory X-Ray Free Electron Laser (PAL-XFEL) and analyze its structure-activity relationship data. The structure demonstrates a unique ligand-binding mode, involving an allosteric subpocket, which clarifies the receptor subtype selectivity and provides a template for structure-based drug design. Together with previously published S1PR structures in complex with antagonists and agonists, the new S1P 5 -inverse agonist structure sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR-family.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2022.02.25.480536

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 68

  1. 10.1002/(SICI)1097-4644(1998)72:30/31+<147::AID-JCB19>3.0.CO;2-F · DOI
  2. 10.1016/j.tcb.2011.09.003 · DOI · Paper page
  3. 10.1159/000362992 · DOI
  4. 10.1158/0008-5472.CAN-05-2001 · DOI
  5. 10.1016/S1043-6618(03)00046-X · DOI
  6. 10.1016/j.cell.2019.04.044 · DOI
  7. 2013, Sphingosine-1-phosphate signaling and cardiac fibrosis, Inflamm. Regen, 33, 96, 10.2492/inflammregen.33.096 · DOI
  8. 10.1074/jbc.275.19.14281 · DOI
  9. 2021, Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner, Sci. Rep, 11, 15308, 10.1038/s41598-021-94052-4 · DOI
  10. 10.3389/fimmu.2017.01242 · DOI
  11. 2015, Discovery of A-971432, an orally bioavailable selective sphingosine-1-phosphate receptor 5 (S1P5) agonist for the potential treatment of neurodegenerative disorders, J. Med. Chem, 58, 9154, 10.1021/acs.jmedchem.5b00928 · DOI
  12. 10.1182/blood-2007-11-121871 · DOI
  13. 10.1136/ejhpharm-2018-001840 · DOI
  14. 2020, The Effectiveness and Value of Siponimod for Secondary Progressive Multiple Sclerosis, J. Manag. Care Spec. Pharm, 26, 236
  15. 2020, Ozanimod: First Approval, Drugs, 80, 841, 10.1007/s40265-020-01319-7 · DOI
  16. 2016, Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity, Br. J. Pharmacol, 173, 1778, 10.1111/bph.13476 · DOI
  17. 2017, Discovery of a 1-Methyl-3,4-dihydronaphthalene-Based Sphingosine-1-Phosphate (S1P) Receptor Agonist Ceralifimod (ONO-4641). A S1P1 and S1P5 Selective Agonist for the Treatment of Autoimmune Diseases, J. Med. Chem, 60, 9508, 10.1021/acs.jmedchem.7b00785 · DOI
  18. 2019, Targeting cytokine signaling and lymphocyte traffic via small molecules in inflammatory bowel disease: JAK inhibitors and S1PR agonists, Front. Pharmacol, 10, 212, 10.3389/fphar.2019.00212 · DOI · Paper page
  19. 10.1038/nchembio804 · DOI · Paper page
  20. 10.1126/science.1215904 · DOI
  21. 10.1126/sciadv.abf5325 · DOI
  22. 2022, Structural insights into sphingosine-1-phosphate recognition and ligand selectivity of S1PR3–Gi signaling complexes, Cell Res, 32, 218, 10.1038/s41422-021-00567-w · DOI
  23. 2021, Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition, Cell Res, 31, 1263, 10.1038/s41422-021-00566-x · DOI
  24. Xu, Z. et al. Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism. Nat. Chem. Biol. https://doi.org/10.1038/s41589-021-00930-3 (2021). · DOI
  25. 10.1016/j.str.2012.04.010 · DOI
  26. 10.1038/nprot.2009.31 · DOI
  27. 10.1016/j.cell.2015.06.002 · DOI
  28. 10.1016/S1043-9471(05)80049-7 · DOI
  29. 2019, Common activation mechanism of class a GPCRs, eLife, 8, e50279, 10.7554/eLife.50279 · DOI
  30. 2021, The role of structural dynamics in GPCR-mediated signaling, FEBS J, 288, 2461, 10.1111/febs.15841 · DOI
  31. 2017, Crystal structures of agonist-bound human cannabinoid receptor CB1, Nature, 55, 468
  32. 10.1038/s41589-019-0387-2 · DOI
  33. 10.1126/science.aay9813 · DOI
  34. 10.1126/science.abf7958 · DOI
  35. 10.1016/j.tibs.2014.03.002 · DOI
  36. 10.1124/pr.119.017863 · DOI
  37. 10.1146/annurev-pharmtox-032112-135923 · DOI
  38. 10.1016/j.tips.2009.02.006 · DOI
  39. 10.1074/jbc.M609648200 · DOI
  40. 10.1073/pnas.202427399 · DOI · Paper page
  41. 10.1038/sj.bjp.0705055 · DOI
  42. 10.1038/s41586-020-2308-7 · DOI · Paper page
  43. 10.1093/nar/gky1015 · DOI · Paper page
  44. Hornik, J. Analysis of naturally occurring genetic variants in the sphingosine–1–phosphate receptor family. PhD Thesis. The Pennsylvania State University, University Park (2019).
  45. 2011, Structural and functional roles of small group-conserved amino acids present on helix-H7 in the β2-adrenergic receptor, Biochim. Biophys. Acta - Biomembranes, 1808, 1170, 10.1016/j.bbamem.2011.01.012 · DOI
  46. 10.1074/jbc.M112.449587 · DOI
  47. 2020, The structural study of mutation-induced inactivation of human muscarinic receptor M4, IUCrJ, 7, 294, 10.1107/S2052252520000597 · DOI
  48. 2020, Protein-water hydrogen-bond networks of G protein-coupled receptors: Graph-based analyses of static structures and molecular dynamics, J. Struct. Biol, 212, 107634, 10.1016/j.jsb.2020.107634 · DOI
  49. Akdel, M. et al. A structural biology community assessment of AlphaFold 2 applications. Preprint at https://www.biorxiv.org/content/10.1101/2021.09.26.461876v1 (2021). · DOI · Paper page
  50. 2013, Lipid Receptor S1P1 Activation Scheme Concluded from Microsecond All-Atom Molecular Dynamics Simulations, PLoS Comput. Biol, 9, e1003261, 10.1371/journal.pcbi.1003261 · DOI
  51. Heo, L. & Feig, M. Multi-State Modeling of G-protein Coupled Receptors at Experimental Accuracy. Preprint at https://www.biorxiv.org/content/10.1101/2021.11.26.470086v1 (2021). · DOI · Paper page
  52. 2021, Could AlphaFold revolutionize chemical therapeutics?, Nat. Struct. Mol. Biol, 28, 771, 10.1038/s41594-021-00670-x · DOI
  53. 10.1016/j.str.2008.02.004 · DOI
  54. 10.1038/ncomms4309 · DOI
  55. 10.1107/S1600576714007626 · DOI
  56. 10.1107/S0021889812002312 · DOI
  57. 10.1107/S0021889807021206 · DOI · Paper page
  58. 10.1107/S0907444910007493 · DOI · Paper page
  59. 10.1107/S0907444912001308 · DOI · Paper page
  60. 10.1002/cpbi.3 · DOI
  61. 10.1002/jcc.20945 · DOI · Paper page
  62. 10.1073/pnas.0902092106 · DOI
  63. 2015, Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers, SoftwareX, 1–2, 19
  64. 10.1016/j.cpc.2013.09.018 · DOI
  65. 10.1038/nmeth.4067 · DOI
  66. 2021, Novel Potent Selective Orally Active S1P5 Receptor Antagonists, ACS Med. Chem. Lett, 12, 351, 10.1021/acsmedchemlett.0c00631 · DOI
  67. 10.1016/bs.mcb.2018.09.014 · DOI
  68. 2012, BRET biosensors to study GPCR biology, pharmacology, and signal transduction, Front. Endocrinol, 3, 105

Metadata

Authors
Lyapina, E., Marin, E., Gusach, A., Orekhov, P., Gerasimov, A., Luginina, A., Vakhrameev, D., Ergasheva, M., Kovaleva, M., Khusainov, G., Khorn, P., Shevtsov, M., Kovalev, K., Okhrimenko, I., Popov, P., Hu, H., Weierstall, U., Liu, W., Cho, Y., Gushchin, I., Rogachev, A., Bourenkov, G., Park, S., Park, G., Hyun, H. J., Park, J., Gordeliy, V., Borshchevskiy, V., Mishin, A., & Cherezov, V.
Affiliations
  • Moscow Institute of Physics and Technology (RU)
  • Vyatka State University (RU)
  • Skolkovo Institute of Science and Technology (RU)
  • Arizona State University (US)
  • Medical College of Wisconsin (US)
  • Pohang University of Science and Technology (KR)
  • European Molecular Biology Laboratory (DE)
  • Centre National de la Recherche Scientifique (FR)
  • University of Southern California (US)
Corresponding author
  • Borshchevskiy, Valentin
  • Mishin, Alexey
  • Cherezov, Vadim
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2022-02-26
Volume
13
Issue
1
Pages
4736-4736
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2022.02.25.480536
PMC
PMC9374744
OpenAlex
W4290839367
Cited by
26
References
1
Citations by year
2026: 5 · 2025: 8 · 2024: 5 · 2023: 5 · 2022: 3
FWCI
1.71
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
  • National Science Foundation (1231306)
  • University of Southern California
  • National Research Foundation
  • Russian Foundation for Basic Research (18-02-40020, 18-02-)
  • Korea Institute of Science and Technology
  • Korea Institute of Science and Technology Information
  • National Research Foundation of Korea (NRF2017M3A9F6029736, - 2017M3A9F6029736)
  • Paul Scherrer Institut
  • Russian Science Foundation (075-15-2021-1354, 22‐74‐10036, 22-24-00454, 075-00337-20-03, 19-14-00261, 20-24-00454)
  • Ministry of Science and Higher Education of the Russian Federation (agreement # 075-00337-20-03, 075–15‐2021–1354, 075-00337-20-03, FSMG-2020-0003, project FSMG‐2020‐0003, 075-15-)
  • Moscow Institute of Physics and Technology
  • Korea Research Environment Open Network
  • Great Southern Development Commission, Government of Western Australia
  • National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
sphingosine-1-phosphate, inverse agonism, receptor subtype selectivity, ligand binding modes, structure-activity relationship, structure-based drug design, receptor activation mechanism
MeSH terms
Humans, Immune System, Lysophospholipids, Sphingosine, Receptors, Lysosphingolipid

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review