Brief Communication

Protein structure determination by combining sparse NMR data with evolutionary couplings

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Abstract

Accurate determination of protein structure by NMR spectroscopy is challenging for larger proteins, for which experimental data are often incomplete and ambiguous. Evolutionary sequence information together with advances in maximum entropy statistical methods provide a rich complementary source of structural constraints. We have developed a hybrid approach (evolutionary coupling–NMR spectroscopy; EC-NMR) combining sparse NMR data with evolutionary residue-residue couplings and demonstrate accurate structure determination for several proteins 6−41 kDa in size.

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References

  1. 1.

    , & Structure 19, 757–766 (2011).

  2. 2.

    , , & J. Am. Chem. Soc. 136, 1893–1906 (2014).

  3. 3.

    , & Biochemistry 36, 1389–1401 (1997).

  4. 4.

    et al. J. Mol. Biol. 300, 197–212 (2000).

  5. 5.

    et al. J. Mol. Biol. 263, 627–636 (1996).

  6. 6.

    et al. PLoS ONE 6, e28766 (2011).

  7. 7.

    et al. Proc. Natl. Acad. Sci. USA 108, E1293–E1301 (2011).

  8. 8.

    et al. Cell 149, 1607–1621 (2012).

  9. 9.

    , & Nat. Biotechnol. 30, 1072–1080 (2012).

  10. 10.

    et al. eLife 3, e03430 (2014).

  11. 11.

    , & eLife 3, e02030 (2014).

  12. 12.

    , , , & Proc. Natl. Acad. Sci. USA 109, 10340–10345 (2012).

  13. 13.

    & Proc. Natl. Acad. Sci. USA 109, E1540–E1547 (2012).

  14. 14.

    et al. J. Mol. Biol. 309, 961–974 (2001).

  15. 15.

    et al. J. Biol. Chem. 286, 39644–39653 (2011).

  16. 16.

    et al. Nature 440, 52–57 (2006).

  17. 17.

    , & Proteins 66, 778–795 (2007).

  18. 18.

    , & J. Am. Chem. Soc. 127, 1665–1674 (2005).

  19. 19.

    , , & Nucleic Acids Res. 40, W542–W546 (2012).

  20. 20.

    , & Nat. Protoc. 1, 749–754 (2006).

  21. 21.

    et al. Science 321, 1206–1210 (2008).

  22. 22.

    et al. Science 327, 1014–1018 (2010).

  23. 23.

    et al. Proc. Natl. Acad. Sci. USA 109, 10873–10878 (2012).

  24. 24.

    , , & Proc. Natl. Acad. Sci. USA 102, 622–627 (2005).

  25. 25.

    , , , & J. Biomol. NMR 40, 95–106 (2008).

  26. 26.

    , , & Proteins 62, 587–603 (2006).

  27. 27.

    , & J. Mol. Biol. 319, 209–227 (2002).

  28. 28.

    , , & Methods Enzymol. 383, 66–93 (2004).

  29. 29.

    PLoS Comput. Biol. 7, e1002195 (2011).

  30. 30.

    & J. Biomol. NMR 4, 171–180 (1994).

  31. 31.

    NMR of Proteins and Nucleic Acids (Wiley, 1986).

  32. 32.

    , & J. Biomol. NMR 54, 181–191 (2012).

  33. 33.

    , , & J. Biomol. NMR 44, 213–223 (2009).

  34. 34.

    , , & Bioinformatics 28, 184–190 (2012).

  35. 35.

    , & Proc. Natl. Acad. Sci. USA 110, 15674–15679 (2013).

  36. 36.

    , , , & Phys. Rev. E 87, 012707 (2013).

  37. 37.

    , & Nat. Rev. Genet. 14, 249–261 (2013).

  38. 38.

    et al. Nucleic Acids Res. 36, D402–D408 (2008).

  39. 39.

    , , , & J. Biomol. NMR 6, 1–10 (1995).

  40. 40.

    , & J. Biomol. NMR 15, 177–180 (1999).

  41. 41.

    & J. Biomol. NMR 56, 227–241 (2013).

  42. 42.

    & J. Am. Chem. Soc. 122, 3791–3792 (2000).

  43. 43.

    & J. Magn. Reson. 167, 228–241 (2004).

  44. 44.

    et al. Proteins 50, 437–450 (2003).

  45. 45.

    , & J. Mol. Biol. 231, 1049–1067 (1993).

  46. 46.

    Proteins 17, 355–362 (1993).

  47. 47.

    , & Nature 356, 83–85 (1992).

  48. 48.

    et al. Proc. Natl. Acad. Sci. USA 105, 4685–4690 (2008).

  49. 49.

    et al. Methods Enzymol. 493, 21–60 (2011).

  50. 50.

    , , & Chem. Rev. 104, 3541–3556 (2004).

  51. 51.

    et al. Methods Enzymol. 394, 111–141 (2005).

  52. 52.

    et al. J. Biol. Chem. 286, 39644–39653 (2011).

  53. 53.

    , & J. Mol. Graphics 14, 51–55 (1996).

  54. 54.

    et al. Structure 21, 1563–1570 (2013).

  55. 55.

    , , , & J. Biomol. NMR 56, 337–351 (2013).

  56. 56.

    , & Chem. Rev. 104, 3519–3540 (2004).

  57. 57.

    Protein Sci. 12, 1–16 (2003).

  58. 58.

    et al. J. Magn. Reson. 143, 402–406 (2000).

  59. 59.

    , , & J. Mol. Biol. 285, 1735–1747 (1999).

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Acknowledgements

We thank all of the members of the Northeast Structural Genomics Consortium who generated and archived NMR spectroscopy data used in this work, particularly scientists in the laboratories of C. Arrowsmith, M. Kennedy, G.T.M., T. Szyperski and J. Prestegard. We thank J. Aramini, G. Liu, G.V.T. Swapna, H. Valafar, M. Nilges and F. Xu for helpful discussions. This work was supported by grants from the US National Institutes of Health grant 1R01-GM106303 to C.S. and D.S.M. and Protein Structure Initiative grant U54-GM094597 to G.T.M.

Author information

Author notes

    • Yuefeng Tang
    •  & Yuanpeng Janet Huang

    These authors contributed equally to this work.

    • Chris Sander
    • , Debora S Marks
    •  & Gaetano T Montelione

    These authors jointly supervised the work.

Affiliations

  1. Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.

    • Yuefeng Tang
    • , Yuanpeng Janet Huang
    •  & Gaetano T Montelione
  2. Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.

    • Yuefeng Tang
    • , Yuanpeng Janet Huang
    •  & Gaetano T Montelione
  3. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.

    • Thomas A Hopf
    •  & Debora S Marks
  4. Department of Informatics, Technische Universität München, Garching, Germany.

    • Thomas A Hopf
  5. Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Chris Sander
  6. Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.

    • Gaetano T Montelione

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Contributions

Y.T., Y.J.H., T.A.H., C.S., D.S.M. and G.T.M. designed the research. Y.J.H. wrote ASDP program code. Y.T., Y.J.H., T.A.H. and D.S.M. performed calculations. Y.T., Y.J.H., T.A.H., C.S., D.S.M. and G.T.M. analyzed data. Y.T., Y.J.H., T.A.H., C.S., D.S.M. and G.T.M. wrote the manuscript.

Competing interests

G.T.M. is associated with Nexomics Biosciences, Inc., a scientific contract research organization.

Corresponding authors

Correspondence to Chris Sander or Debora S Marks or Gaetano T Montelione.

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    Supplementary Figures 1–12, Supplementary Tables 1–6 and Supplementary Notes 1–5