Skip to main content
SpringerLink
Log in

X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death

  • Letter
  • Published:

From Nature

View current issue Submit your manuscript

Abstract

THE Bcl-2 family of proteins regulate programmed cell death by an unknown mechanism1. Here we describe the crystal and solution structures of a Bcl-2 family member, Bcl-xL (ref. 2). The structures consist of two central, primarily hydrophobic α-helices, which are surrounded by amphipathic helices. A 60-residue loop connecting helices αl and α2 was found to be flexible and non-essential for anti-apoptotic activity. The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3)3–5 are in close spatial proximity and form an elongated hydrophobic cleft that may represent the binding site for other Bcl-2 family members. The arrangement of the α-helices in Bcl-xL is reminiscent of the membrane translocation domain of bacterial toxins, in particular diphtheria toxin and the colicins6. The structural similarity may provide a clue to the mechanism of action of the Bcl-2 family of proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Korsmeyer, S. J. Trends Genet. 11, 101–105 (1995).

    Article  CAS  Google Scholar 

  2. Boise, L. H. et al. Cell 74, 597–608 (1993).

    Article  CAS  Google Scholar 

  3. Yin, X.-M., Oltvai, Z. N. & Korsmeyer, S. J. Nature 369, 321–323 (1994).

    Article  ADS  CAS  Google Scholar 

  4. Chittenden, T. et al. EMBO J. 14, 5589–5596 (1995).

    Article  CAS  Google Scholar 

  5. Boyd, J. M. et al. Oncogens 11, 1921–1928 (1995).

    CAS  Google Scholar 

  6. Parker, M. W. & Pattus, F. Trends biochem. Sci. 18, 391–395 (1993).

    Article  CAS  Google Scholar 

  7. Cheng, E. H.-Y., Levine, B., Boise, L. H., Thompson, C. B. & Hardwick, J. M. Nature 379, 554–557 (1996).

    Article  ADS  CAS  Google Scholar 

  8. Borner, C. J. Cell Biol. 126, 1059–1068 (1994).

    Article  CAS  Google Scholar 

  9. Hanada, M., Aime-Sempe, C., Sato, T. & Reed, J. C. J. biol. Chem. 270, 11962–11969 (1995).

    Article  CAS  Google Scholar 

  10. Sedlak, T. W. et al. Proc. natn. Acad. of Sci. U.S.A. 92, 7834–7838 (1995).

    Article  ADS  CAS  Google Scholar 

  11. Yang, E. et al. Cell 80, 285–291 (1995).

    Article  CAS  Google Scholar 

  12. London, E. Biochim. biophys. Acta 1113, 25–51 (1992).

    Article  CAS  Google Scholar 

  13. Lam, M. et al. Proc. natn. Acad. Sci. U.S.A. 91, 6569–6573 (1994).

    Article  ADS  CAS  Google Scholar 

  14. Zamzami, et al. J. exp. Med. 182, 367–377 (1995).

    Article  CAS  Google Scholar 

  15. Carson, M. J. J. Molec. Graph. 5, 103–106 (1987).

    Article  CAS  Google Scholar 

  16. Fang, W., Rivard, J. J., Mueller, D. L. & Behrens, T. W. J. Immunol. 153, 4388–4398 (1994).

    CAS  PubMed  Google Scholar 

  17. Otwinowski, Z. Proceedings of the CCP4 Study Weekend: Isomorphous Replacement and Anomalous Scattering (eds Wolf, W., Evans, P. R. & Leslie, A. G. W.) 80–86 (SERC Daresbury Laboratory, Warrington, UK, 1991).

    Google Scholar 

  18. CCP4: A Suite of Programs for Protein Crystallography (SERC Daresbury Laboratory, Warrington, UK, 1979).

  19. Jones, T. A., Zou, J.-Y., Cowan, S. W. & Kjelgaard, M. Acta crystallogr. A 47, 110 (1991).

    Article  Google Scholar 

  20. Reed, R. J. Acta crystallogr. A 42, 140–149 (1986).

    Article  Google Scholar 

  21. Brünger, A. T. X-PLOR 3.1 (Yale University, New Haven, CT, 1992).

    Google Scholar 

  22. Yamazaki, T., Lee, W., Arrowsmith, S. H., Muhandiram, D. R. & Kay, L. E. J. Am. chem. Soc. 116, 11655–11666 (1994).

    Article  CAS  Google Scholar 

  23. Clore, G. M. & Gronenborn, A. M. Meth. Enzym. 239, 349–363 (1994).

    Article  CAS  Google Scholar 

  24. Logan, T. M., Olejniczak, E. T., Xu, R. X. & Fesik, S. W. FEBS Lett. 314, 413–418 (1992).

    Article  CAS  Google Scholar 

  25. Neri, D., Szperski, T., Otting, G., Senn, H. & Wüthrich, K. Biochemistry 28, 7510–7516 (1989).

    Article  CAS  Google Scholar 

  26. Vuister, G. W., Kim, S.-J., Wu, C. & Bax, A. J. Am. chem. Soc. 116, 9206–9210 (1994).

    Article  CAS  Google Scholar 

  27. Kuboniwa, H., Grzesiek, S., Delaglio, F. & Bax, A. J. Biomolec. NMR 4, 871–878 (1994).

    Article  CAS  Google Scholar 

  28. Kuszewski, J., Nilges, M. & Brünger, A. T. J. Biomolec. NMR 2, 33–56 (1992).

    Article  CAS  Google Scholar 

  29. Farrow, N. A. et al. Biochemistry 33, 5984–6003 (1994).

    Article  CAS  Google Scholar 

  30. Choe, S. et al. Nature 357, 216–222 (1992).

    Article  ADS  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Sui-Lam Wong

    Present address: Department of Biological Sciences, Division of Cellular, Molecular and Microbial Biology, University of Calgary, Calgary, Alberta, T2N 1N4, Canada

Authors and Affiliations

  1. Protein Crystallography, Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois, 60064, USA

    Steven W. Muchmore

  2. NMR Research, Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois, 60064, USA

    Michael Sattler, Heng Liang, John E. Harlan, Ho Sup Yoon, David Nettesheim & Stephen W. Fesik

  3. Research Computing and Information Sciences, Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois, 60064, USA

    Robert P. Meadows

  4. Aging and Degenerative Diseases Research, Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois, 60064, USA

    Sui-Lam Wong & Shi-Chung Ng

  5. Howard Hughes Medical Institute,

    Brian S. Chang & Craig B. Thompson

  6. Departments of Medicine, Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois, 60637, USA

    Brian S. Chang & Craig B. Thompson

Authors
  1. Steven W. Muchmore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Sattler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heng Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert P. Meadows
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John E. Harlan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ho Sup Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David Nettesheim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Brian S. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Craig B. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sui-Lam Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shi-Chung Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Stephen W. Fesik
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Muchmore, S., Sattler, M., Liang, H. et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 381, 335–341 (1996). https://doi.org/10.1038/381335a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/381335a0

  • Springer Nature Limited

This article is cited by

Search

Navigation