Advertisement

Journal of Chemical Crystallography

, Volume 41, Issue 4, pp 470–480 | Cite as

The Neutron Structure of the Formyl Peptide Receptor Antagonist Cyclosporin H (CsH) Unambiguously Determines the Solvent and Hydrogen-Bonding Structure for Crystal Form II

  • Anna S. Gardberg
  • Brian S. Potter
  • Rex A. Palmer
  • Garry J. McIntyre
  • Dean A. A. Myles
ORIGINAL PAPER

Abstract

Single-crystal neutron diffraction data were collected at 20 K to a resolution of 1.05 Å on a crystal of the inverse formyl peptide receptor agonist cyclosporin H, CsH, (crystal form II, CsH-II) on the Laue diffractometer VIVALDI at the Institut Laue-Langevin (Grenoble). The solvent structure and hydrogen bonding network of CsH-II have been unambiguously determined by single-crystal neutron diffraction; the agreement factor R(F 2) is 13.5% for all 2726 reflections. All hydrogen atom positions, including methyl-group orientations, have been determined by crystallographic refinement. The neutron structure of cyclosporin provides unique and complementary insights into methyl orientation, hydrogen-bonding, and solvent interactions that are not available from X-ray analysis alone.

Index Abstract

CsH neutron structure showing the 7 waters and trace of the main chain N1---N11. All water hydrogens were determined experimentally. Thermal ellipsoids are plotted at 85% probability. Drawn with ORTEP-III/RASTER (Burnett and Johnson, Report ORNL-6895, 1996; Merritt and Bacon, Methods in Enzymology 277:505, 1997) as implemented in the program suite WinGX (Farrugia, Journal of Applied Crystallography 32(4):837, 1999) and generated by ORTEP-3 for Windows (Farrugia, Journal of Applied Crystallography 30(5):565, 1997). The main chain trace was drawn with RASMOL (Sayle, Glaxo research and development, 1994).

Keywords

Cyclosporin H Neutron structure Water hydrogens Hydrogen bonding Laue diffraction 

Notes

Acknowledgments

We gratefully acknowledge the ILL for the provision of beamtime. We thank Professor Jon Cooper for his help and interest in the early stages of this study. We thank Ray Simpson for depicting the main chain trace shown in the Index Abstract figure. This research at Oak Ridge National Laboratory’s Center for Structural Molecular Biology (CSMB) was supported by the Office of Biological and Environmental Research, using facilities supported by the US Department of Energy, managed by UT-Battelle, LLC under contract No.DE-AC05-00OR22725. This research was supported in part by an appointment to the ORNL Postdoctoral Research Associates Program at the Oak Ridge National Laboratory, sponsored by the US Department of Energy and administered by the Oak Ridge Institute for Science and Education.

References

  1. 1.
    Ko SY, Dalvit C (1992) Int J Pept Protein Res 40(5):380CrossRefGoogle Scholar
  2. 2.
    Loosli HR, Kessler H, Oschkinat H, Weber HP, Petcher TJ, Widmer A (1985) Helvetica Chimica Acta 68(3):682CrossRefGoogle Scholar
  3. 3.
    Altschuh D, Vix O, Rees B, Thierry JC (1992) Science 256(5053):92CrossRefGoogle Scholar
  4. 4.
    Fesik SW, Gampe RT, Eaton HL, Gemmecker G, Olejniczak ET, Neri P, Holzman TF, Egan DA, Edalji R, Simmer R, Helfrich R, Hochlowski J, Jackson M (1991) Biochemistry 30(26):6574CrossRefGoogle Scholar
  5. 5.
    Fesik SW, Neri P, Meadows R, Olejniczak ET, Gemmecker G (1992) J Am Chem Soc 114(8):3165CrossRefGoogle Scholar
  6. 6.
    Kallen J, Mikol V, Taylor P, Walkinshaw MD (1998) J Mol Biol 283(2):435CrossRefGoogle Scholar
  7. 7.
    Kessler H, Kock M, Wein T, Gehrke M (1990) Helvetica Chimica Acta 73(7):1818CrossRefGoogle Scholar
  8. 8.
    Knott RB, Schefer J, Schoenborn BP (1990) Acta Crystallogr C Cryst Struct Commun 46:1528CrossRefGoogle Scholar
  9. 9.
    Mikol V, Taylor P, Kallen J, Walkinshaw MD (1998) J Mol Biol 283(2):451CrossRefGoogle Scholar
  10. 10.
    Weber C, Wider G, von Freyberg B, Traber R, Braun W, Widmer H, Wuthrich K (1991) Biochemistry 30(26):6563CrossRefGoogle Scholar
  11. 11.
    Wuthrich K, Vonfreyberg B, Weber C, Wider G, Traber R, Widmer H, Braun W (1991) Science 254(5034):953CrossRefGoogle Scholar
  12. 12.
    Potter B, Palmer RA, Withnall R, Jenkins TC, Chowdhry BZ (2003) Org Biomol Chem 1(9):1466CrossRefGoogle Scholar
  13. 13.
    McIntyre GJ, Lemée-Cailleau M-H, Wilkinson C (2006) Phys B: Condens Matter 385–386:1055CrossRefGoogle Scholar
  14. 14.
    Wilkinson C, Cowan JA, Myles DAA, Cipriani F, McIntyre GJ (2002) Neutron News 13:37CrossRefGoogle Scholar
  15. 15.
    Campbell JW, Hao Q, Harding MM, Nguti ND, Wilkinson C (1998) J Appl Crystallogr 31(3):496CrossRefGoogle Scholar
  16. 16.
    Wilkinson C, Khamis HW, Stansfield RFD, McIntyre GJ (1988) J Appl Crystallogr 21:471CrossRefGoogle Scholar
  17. 17.
    Arzt S, Campbell JW, Harding MM, Hao Q, Helliwell JR (1999) J Appl Crystallogr 32(3):554CrossRefGoogle Scholar
  18. 18.
    Evans PR (2006) Acta Crystallogr D Biol Cryst 62:72–82CrossRefGoogle Scholar
  19. 19.
    Brunger AT (1992) Nature 355(6359):472CrossRefGoogle Scholar
  20. 20.
    Brunger AT (1997) Methods Enzymol 277:366CrossRefGoogle Scholar
  21. 21.
    Sheldrick GM (2008) Acta Crystallogr A 64(Pt 1):112CrossRefGoogle Scholar
  22. 22.
    Sears VF (1992) Neutron News 3(3):26CrossRefGoogle Scholar
  23. 23.
    Stegmann C, Seeliger D, Sheldrick G, de Groot B, Wahl M (2009) Angewandte Chemie (International ed. in English)Google Scholar
  24. 24.
    Sayle R (1994) Glaxo research and development. Greenfield, Middlesex, UKGoogle Scholar
  25. 25.
    Vaguine AA, Richelle J, Wodak SJ (1999) Acta Crystallogr D Biol Crystallogr 55(Pt 1):191CrossRefGoogle Scholar
  26. 26.
    Burnett M, Johnson C (1996) Report ORNL-6895, Oak Ridge National Laboratory, Oak Ridge, TN, USA Google Scholar
  27. 27.
    Farrugia L (1997) J Appl Crystallogr 30(5):565CrossRefGoogle Scholar
  28. 28.
    Merritt E, Bacon D (1997) Methods Enzymol 277:505CrossRefGoogle Scholar
  29. 29.
    Farrugia L (1999) J Appl Crystallogr 32(4):837CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2010

Authors and Affiliations

  • Anna S. Gardberg
    • 1
    • 4
  • Brian S. Potter
    • 2
  • Rex A. Palmer
    • 2
  • Garry J. McIntyre
    • 3
    • 5
  • Dean A. A. Myles
    • 1
  1. 1.Oak Ridge National LaboratoryOak RidgeUSA
  2. 2.School of Crystallography, Birkbeck College, University of LondonLondonUK
  3. 3.Institut Max von Laue–Paul LangevinGrenoble Cedex 9France
  4. 4.Emerald BioStructuresBainbridge IslandUSA
  5. 5.Australian Nuclear Science and Technology OrganisationLucas HeightsAustralia

Personalised recommendations