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.

  • Progress
  • Published:

Structural genomics: beyond the Human Genome Project

Abstract

With access to whole genome sequences for various organisms and imminent completion of the Human Genome Project, the entire process of discovery in molecular and cellular biology is poised to change. Massively parallel measurement strategies promise to revolutionize how we study and ultimately understand the complex biochemical circuitry responsible for controlling normal development, physiologic homeostasis and disease processes. This information explosion is also providing the foundation for an important new initiative in structural biology. We are about to embark on a program of high-throughput X-ray crystallography aimed at developing a comprehensive mechanistic understanding of normal and abnormal human and microbial physiology at the molecular level. We present the rationale for creation of a structural genomics initiative, recount the efforts of ongoing structural genomics pilot studies, and detail the lofty goals, technical challenges and pitfalls facing structural biologists.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3: Flowchart depicting the processes involved in high-throughput structural genomics using X-ray crystallography.

Similar content being viewed by others

References

  1. Brenner, S.E., Chothia, C. & Hubbard, T. Population statistics of protein structures: lessons from structural classifications. Curr. Opin. Struct. Biol. 7, 369–376 (1997).

    Article  CAS  Google Scholar 

  2. Orengo, C.A. et al. The CATH Database provides insights into protein structure/function relationship. Nucleic Acids Res. 27, 275 –279 (1999).

    Article  CAS  Google Scholar 

  3. Fischer, D. & Eisenberg, D. Assigning folds to the proteins encoded by the genome of Mycoplasma genitalium. Proc. Natl Acad. Sci. USA 94, 11929–11934 (1997).

    Article  CAS  Google Scholar 

  4. Rychlewski, L., Zhang, B. & Godzik, A. Fold and function predictions for Mycoplasma genitalium proteins. Fold. Des. 3, 229– 238 (1998).

    Article  CAS  Google Scholar 

  5. Huynen, M. et al. Homology-based fold predictions for Mycoplasma genitalium proteins. J. Mol. Biol. 280, 323– 326 (1998).

    Article  CAS  Google Scholar 

  6. Sanchez, R. & Sali, A. Large-scale protein structure modeling of the Saccharomyces cerevisiae genome. Proc. Natl Acad. Sci. USA 95, 13597–13602 (1998).

    Article  CAS  Google Scholar 

  7. Gaasterland, T. Structural genomics taking shape. Trends Genet. 14, 135 (1998).

    Article  CAS  Google Scholar 

  8. Sali, A. 100,000 protein structures for the biologist. Nature Struct. Biol. 5, 1029–1032 (1998).

    Article  CAS  Google Scholar 

  9. Studier, F.W., Rosenberg, A.H., Dunn, J.J. & Dubendorff, J.W. Use of T7 RNA polymerase to direct expression of cloned genes. Methods Enzymol. 185, 60–89 (1990).

    Article  CAS  Google Scholar 

  10. Holm, L. & Sander, C. A review of the use of protein structure comparison in protein classification and function identification. Science 273, 595–602 ( 1996).

    Article  CAS  Google Scholar 

  11. Cohen, S.L., Ferre-D'Amare, A.R., BFey, S.K. & Chait, B.T. Probing the solution structure of the DNA-binding protein Max by a combination of proteolysis and mass spectrometry. Protein Sci. 4, 1088–1099 (1995).

    Article  CAS  Google Scholar 

  12. Cohen, S.L. Domain elucidation by mass spectrometry. Structure 4, 1013–1016 (1996).

    Article  CAS  Google Scholar 

  13. Xie, X. et al. Structural similarity between TAFs and the heterotetrameric core of the histone octamer. Nature 380, 316–322 (1996).

    Article  CAS  Google Scholar 

  14. Sanchez, R. & Sali, A. Comparative proteins structure modeling in genomics. J. Comp. Phys. 151, 388– 401 (1999).

    Article  CAS  Google Scholar 

  15. Wallace, A.C., Borkakoti, N. & Thornton, J.M. TESS: a geometric hashing algorithm for deriving 3D coordinate templates for searching structural databases. Application to enzyme active sites. Protein Sci. 6, 2308– 2323 (1997).

    Article  CAS  Google Scholar 

  16. Fetrow, J.S., Godzik, A. & Skolnick, J. Functional analysis of the Eschericia coli genome using the sequence-to-structure-to-function paradigm: identification of proteins exhibiting the glutaredoxin/thioredoxin disulfide oxidoreductase activity. J. Mol. Biol. 282, 703– 711 (1998).

    Article  CAS  Google Scholar 

  17. Clark, K.L., Halay, E.D., Lai, E. & Burley, S.K. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 364, 412–420 ( 1993).

    Article  CAS  Google Scholar 

  18. Lai, E., Clark, K.L., Burley, S. & Darnell, J.E. Hepatocyte nuclear factor 3/fork head or "winged helix" proteins: a family of transcription factors of diverse biological function. Proc. Natl Acad. Sci. USA 90, 10421–10423 (1993).

    Article  CAS  Google Scholar 

  19. Yang, F., Gustafson, K.R., Boyd, M.R. & Wlodawer, A. Crystal structure of Escherichia coli Hdea. Nature Struct. Biol. 5, 763–764 ( 1998).

    Article  CAS  Google Scholar 

  20. Guenther, B.D., et al. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nature Struct. Biol. 6, 359– 365 (1999).

    Article  CAS  Google Scholar 

  21. Deo, R.C., Bonanno, J.B., Sonenberg, N. & Burley S.K. Recognition of polyadenylate RNA by the poly(A)-binding protein. Cell (in press).

Download references

Acknowledgements

This work was supported in part by the National Institutes of Health Center for Research Resources, the Department of Energy, Albert Einstein College of Medicine and The Rockefeller University. S.K.B. is an Investigator in the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen K Burley.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burley, S., Almo, S., Bonanno, J. et al. Structural genomics: beyond the Human Genome Project. Nat Genet 23, 151–157 (1999). https://doi.org/10.1038/13783

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/13783

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing