Abstract
Technical advances on several frontiers have expanded the applicability of existing methods in structural biology and helped close the resolution gaps between them. As a result, we are now poised to integrate structural information gathered at multiple levels of the biological hierarchy — from atoms to cells — into a common framework. The goal is a comprehensive description of the multitude of interactions between molecular entities, which in turn is a prerequisite for the discovery of general structural principles that underlie all cellular processes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Alberts, B. The cell as a collection of protein machines — preparing the next generation of molecular biologists. Cell 92, 291–294 (1998).
Baumeister, W. & Steven, A. C. Macromolecular electron microscopy in the era of structural genomics. Trends Biochem. Sci. 25, 624–631 (2000).
Sali, A. & Kuriyan, J. Challenges at the frontiers of structural biology. Trends Biochem. Sci. 24, M20–M24 (1999).
Orengo, C. A. et al. The CATH protein family database: a resource for structural and functional annotation of genomes. Proteomics 2, 11–21 (2002).
Govindarajan, S., Recabarren, R. & Goldstein, R. A. Estimating the total number of protein folds. Proteins 35, 408–414 (1999).
Marcotte, E. M., Pellegrini, M., Thompson, M. J., Yeates, T. O. & Eisenberg, D. A combined algorithm for genome-wide prediction of protein function. Nature 402, 83–86 (1999).
Mewes, H. W. et al. MIPS: a database for genomes and protein sequences. Nucleic Acids Res. 30, 31–34 (2002).
Costanzo, M. C. et al. YPD, PombePD and WormPD: model org anism volumes of the BioKnowledge library, an integrated resource for protein information. Nucleic Acids Res. 29, 75–79 (2001).
von Mering, C. et al. Comparative assessment of large-scale data sets of protein–protein interactions. Nature 417, 399–403 (2002).
Ito, T. et al. A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc. Natl Acad. Sci. USA 98, 4569–4574 (2001).
Uetz, P. et al. A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae. Nature 403, 623–627 (2000).
Aloy, P. & Russell, R. B. Potential artefacts in protein-interaction networks. FEBS Lett. 530, 253–254 (2002).
Gavin, A. C. et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141–147 (2002).
Aloy, P. & Russell, R. B. The third dimension for protein interactions and complexes. Trends Biochem. Sci. 27, 633–638 (2002).
Jansen, R., Greenbaum, D. & Gerstein, M. Relating whole-genome expression data with protein-protein interactions. Genome Res. 2, 37–46 (2002).
Ge, H., Liu, Z., Church, G. M. & Vidal, M. Correlation between transcriptome and interactome mapping data from Saccharomyces cerevisiae. Nature Genet. 4, 482–486 (2001).
Edwards, A. M. et al. Bridging structural biology and genomics: assessing protein interaction data with known complexes. Trends Genet. 10, 529–536 (2002).
Kumar, A. & Snyder, M. Protein complexes take the bait. Nature 415, 123–124 (2002).
Abbott, A. The society of proteins. Nature 417, 894–896 (2002).
Westbrook, J. et al. The Protein Data Bank: unifying the archive. Nucleic Acids Res. 30, 245–248 (2002).
Cramer, P., Bushnell, D. A. & Kornberg, R. D. Structural basis of transcription: RNA polymerase II at 2.8 Ångstrom resolution. Science 292, 1863–1876 (2001).
Ban, N., Nissen, P., Hansen, J., Moore, P. B. & Steitz, T. A. The complete atomic structure of the large ribosomal subunit at 2.4 Å resolution. Science 289, 905–920 (2000).
Harms, J. et al. High resolution structure of the large ribosomal subunit from a mesophilic eubacterium. Cell 107, 679–688 (2001).
Wimberly, B. T. et al. Structure of the 30S ribosomal subunit. Nature 407, 327–339 (2000).
Yusupov, M. M. et al. Crystal structure of the ribosome at 5.5 Å resolution. Science 292, 883–896 (2001).
Abola, E., Kuhn, P., Earnest, T. & Stevens, R. C. Automation of X-ray crystallography. Nature Struct. Biol. 7, 973–977 (2000).
Snell, G. et al. Automatic sample mounting and alignment system for biological crystallography. J. Synchrotron Radiat. (in the press).
Burley, S. K. et al. Structural genomics: beyond the Human Genome Project. Nature Genet. 23, 151–157 (1999).
Vitkup, D., Melamud, E., Moult, J. & Sander, C. Completeness in structural genomics. Nature Struct. Biol. 8, 559–566 (2001).
Structural genomics. Nature Struct. Biol. 7 (Suppl.), 927–994 (2000).
Frank, J. Three-dimensional Electron Microscopy of Macromolecular Assemblies (Academic, London, 1996).
Henderson, R., Baldwin, J. M. & Ceska, T. A. Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. J. Mol. Biol. 213, 899–929 (1990).
Kuhlbrandt, W., Wang, D. N. & Fujiyoshi, Y. Atomic model of plant light-harvesting complex by electron crystallography. Nature 367, 614–621 (1994).
Grigorieff, N., Ceska, T. A., Downing, K. H., Baldwin, J. M. & Henderson, R. Electron-crystallographic refinement of the structure of bacteriorhodopsin. J. Mol. Biol. 259, 393–421 (1996).
Nogales, E., Wolf, S. G. & Downing, K. H. Structure of the αβ tubulin dimer by electron crystallography. Nature 391, 199–203 (1998).
Mitsuoka, K. et al. The structure of bacteriorhodopsin at 3.0 Å resolution based on electron crystallography: implication of the charge distribution. J. Mol. Biol. 286, 861–882 (1999).
Murata, K. et al. Structural determinants of water permeation through aquaporin-1. Nature 407, 599–605 (2000).
Lowe, J., Li, H., Downing, K. H. & Nogales, E. Refined structure of αβ-tubulin at 3.5 Å resolution. J. Mol. Biol. 313, 1045–1057 (2001).
Conway, J. F. et al. Visualization of a 4-helix bundle in the hepatitis B virus capsid by cryo-electron microscopy. Nature 386, 91–94 (1997).
Bottcher, B., Wynne, S. A. & Crowther, R. A. Determination of the fold of the core protein of hepatitis B virus by cryo-electron microscopy. Nature 386, 88–91 (1997).
Li, H. L., DeRosier, D. J., Nicholson, W. V., Nogales, E. & Downing, K. H. Microtubule structure at 8 Å resolution. Structure 10, 1317–1328 (2002).
Rockel, B., Peters, J., Kuhlmorgen, B., Glaeser, R. M. & Baumeister, W. A giant protease with a twist: the TPP II complex from Drosophila studied by electron microscopy. EMBO J. 21, 5979–5984 (2002).
Henderson, R. The potential and limitations of neutrons, electrons and X-rays for atomic resolution microscopy of unstained biological molecules. Q. Rev. Biophys. 28, 171–193 (1995).
Carragher, B. et al. Leginon: an automated system for acquisition of images from vitreous ice specimens. J. Struct. Biol 132, 33–45 (2000).
Zhang, P. J., Beatty, A., Milne, J. L. S. & Subramaniam, S. Automated data collection with a Tecnai 12 electron microscope: applications for molecular imaging by cryomicroscopy. J. Struct. Biol. 135, 251–261 (2001).
Zhu, Y. X., Carragher, B., Kriegman, D. J., Milligan, R. A. & Potter, C. S. Automated identification of filaments in cryoelectron microscopy images. J. Struct. Biol. 135, 302–312 (2001).
Rossmann, M. G., Bernal, R. & Pletnev, S. V. Combining electron microscopic with X-ray crystallographic structures. J. Struct. Biol. 136, 190–200 (2001).
Wriggers, W. & Birmanns, S. Using Situs for flexible and rigid-body fitting of multiresolution single-molecule data. J. Struct. Biol. 133, 193–202 (2001).
Volkmann, N. & Hanein, D. Quantitative fitting of atomic models into observed densities derived by electron microscopy. J. Struct. Biol. 125, 176–184 (1999).
Chacon, P. & Wriggers, W. Multi-resolution contour-based fitting of macromolecular structures. J. Mol. Biol. 317, 375–384 (2002).
Malhotra, A., Tan, R. K. & Harvey, S. C. Prediction of the three-dimensional structure of Escherichia coli 30S ribosomal subunit: a molecular mechanics approach. Proc. Natl Acad. Sci. USA 87, 1950–1954 (1990).
Aloy, P. et al. A complex prediction: three-dimensional model of the yeast exosome. EMBO Rep. 3, 628–635 (2002).
Spahn, C. M. et al. Structure of the 80S ribosome from Saccharomyces cerevisiae–tRNA-ribosome and subunit-subunit interactions. Cell 107, 373–386 (2001).
Baumeister, W. Electron tomography: towards visualizing the molecular organization of the cytoplasm. Curr. Opin. Struct. Biol. 12, 679–684 (2002).
Baumeister, W., Grimm, R. & Walz, J. Electron tomography of molecules and cells. Trends Cell Biol. 9, 81–85 (1999).
Medalia, O. et al. Macromolecular architecture in eukaryotic cells visualized by cryoelectron tomography. Science 298, 1209–1213 (2002).
Grunewald, K., Medalia, O., Gross, A., Steven, A. & Baumeister, W. Prospects of electron cryotomography to visualize macromolecular complexes inside cellular compartments: implications of crowding. Biophys. Chem. (in press).
Bohm, J. et al. Toward detecting and identifying macromolecules in a cellular context: template matching applied to electron tomograms. Proc. Natl Acad. Sci. USA 97, 14245–14250 (2000).
Frangakis, A. S. et al. Identification of macromolecular complexes in electron cryotomograms of phantom cells. Proc. Natl Acad. Sci. USA 99, 14153–14158 (2002).
Grimm, R. et al. Electron tomography of ice-embedded prokaryotic cells. Biophys. J. 74, 1031–1042 (1998).
Plitzko, J. et al. In vivo veritas: electron cryotomography of cells. Trends Biotechnol. 20, S40–S44 (2002).
Koster, A. J. et al. Perspectives of molecular and cellular electron tomography. J. Struct. Biol. 120, 276–308 (1997).
Glaeser, R. M. Electron crystallography: present excitement, a nod to the past, anticipating the future. J. Struct. Biol. 128, 3–14 (1999).
Zhang, G. Y. et al. Crystal structure of Thermus aquaticus core RNA polymerase at 3.3 Å resolution. Cell 98, 811–824 (1999).
Fiaux, J., Bertelsen, E. B., Horwich, A. L. & Wuthrich, K. NMR analysis of a 900K GroEL–GroES complex. Nature 418, 207–211 (2002).
Yee, A. et al. An NMR approach to structural proteomics. Proc. Natl Acad. Sci. USA 99, 1825–1830 (2002).
Fushman, D., Xu, R. & Cowburn, D. Direct determination of changes of interdomain orientation on ligation: use of the orientational dependence of 15N NMR relaxation in Abl SH(32). Biochemistry 38, 10225–10230 (1999).
Nakanishi, T. et al. Determination of the interface of a large protein complex by transferred cross-saturation measurements. J. Mol. Biol. 318, 245–249 (2002).
Pellecchia, M., Sem, D. S. & Wuthrich, K. NMR in drug discovery. Nature Rev. Drug Discov. 1, 211–219 (2002).
Frank, J. Single-particle imaging of macromolecules by cryo-electron microscopy. Annu. Rev. Biophys. Biomol. Struct. 31, 303–319 (2002).
Volkmann, N. A novel three-dimensional variant of the watershed transform for segmentation of electron density maps. J. Struct. Biol. 138, 123–129 (2002).
Rout, M. P. et al. The yeast nuclear pore complex: composition, architecture, and transport mechanism. J. Cell Biol. 148, 635–651 (2000).
Rappsilber, J., Siniossoglou, S., Hurt, E. C. & Mann, M. A generic strategy to analyze the spatial organization of multi-protein complexes by cross-linking and mass spectrometry. Anal. Chem. 72, 267–275 (2000).
Young, M. M. et al. High throughput protein fold identification by using experimental constraints derived from intramolecular cross-links and mass spectrometry. Proc. Natl Acad. Sci. USA 97, 5802–5806 (2000).
Neubauer, G. et al. Identification of the proteins of the yeast U1 small nuclear ribonucleoprotein complex by mass spectrometry. Proc. Natl Acad. Sci. USA 94, 385–390 (1997).
Neubauer, G. et al. Mass spectrometry and EST-database searching allows characterization of the multi-protein spliceosome complex. Nature Genet. 20, 46–50 (1998).
Houry, W. A., Frishman, D., Eckerskorn, C., Lottspeich, F. & Hartl, F. U. Identification of in vivo substrates of the chaperonin GroEL. Nature 402, 147–154 (1999).
Ho, Y. et al. Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415, 180–183 (2002).
Miras, I., Schaeffer, F., Beguin, P. & Alzari, P. M. Mapping by site-directed mutagenesis of the region responsible for cohesin-dockerin interaction on the surface of the seventh cohesin domain of Clostridium thermocellum CipA. Biochemistry 41, 2115–2119 (2002).
Wells, J. A. Systematic mutational analyses of protein-protein interfaces. Methods Enzymol. 202, 390–411 (1991).
Jin, L., Cohen, F. E. & Wells, J. A. Structure from function: screening structural models with functional data. Proc. Natl Acad. Sci. USA 91, 113–117 (1994).
Schena, M., Shalon, D., Davis, R. W. & Brown, P. O. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270, 467–470 (1995).
Lockhart, D. J. & Winzeler, E. A. Genomics, gene expression and DNA arrays. Nature 405, 827–836 (2000).
Baker, D. & Sali, A. Protein structure prediction and structural genomics. Science 294, 93–96 (2001).
Bonneau, R. & Baker, D. Ab initio protein structure prediction: progress and prospects. Annu. Rev. Biophys. Biomol. Struct. 30, 173–189 (2001).
Bonneau, R. et al. De novo prediction of three-dimensional structures for major protein families. J. Mol. Biol. 322, 65–78 (2002).
Marti-Renom, M. A. et al. Comparative protein structure modeling of genes and genomes. Annu. Rev. Biophys. Biomol. Struct. 29, 291–325 (2000).
Domingues, F. S., Lackner, P., Andreeva, A. & Sippl, M. J. Structure-based evaluation of sequence comparison and fold recognition alignment accuracy. J. Mol. Biol 297, 1003–1013 (2000).
Pieper, U., Eswar, N., Stuart, A. C., Ilyin, V. A. & Sali, A. MODBASE, a database of annotated comparative protein structure models. Nucleic Acids Res. 30, 255–259 (2002).
Smith, G. R. & Sternberg, M. J. E. Prediction of protein-protein interactions by docking methods. Curr. Opin. Struct. Biol. 12, 28–35 (2002).
Strynadka, N. C. J. et al. Molecular docking programs successfully predict the binding of a β-lactamase inhibitory protein to TEM-1 β-lactamase. Nature Struct. Biol. 3, 233–239 (1996).
Enright, A. J., Iliopoulos, I., Kyrpides, N. C. & Ouzounis, C. A. Protein interaction maps for complete genomes based on gene fusion events. Nature 402, 86–90 (1999).
Overbeek, R., Fonstein, M., D'Souza, M., Pusch, G. D. & Maltsev, N. The use of gene clusters to infer functional coupling. Proc. Natl Acad. Sci. USA 96, 2896–2901 (1999).
Goh, C. S., Bogan, A. A., Joachimiak, M., Walther, D. & Cohen, F. E. Co-evolution of proteins with their interaction partners. J. Mol. Biol. 299, 283–293 (2000).
Pazos, F. & Valencia, A. Similarity of phylogenetic trees as indicator of protein-protein interaction. Protein Eng. 14, 609–614 (2001).
Pazos, F. & Valencia, A. In silico two-hybrid system for the selection of physically interacting protein pairs. Proteins 47, 219–227 (2002).
Lichtarge, O., Bourne, H. R. & Cohen, F. E. An evolutionary trace method defines binding surfaces common to protein families. J. Mol. Biol. 257, 342–358 (1996).
Lappe, M., Park, J., Niggemann, O. & Holm, L. Generating protein interaction maps from incomplete data: application to fold assignment. Bioinformatics 17, S149–S156 (2001).
Aloy, P. & Russell, R. B. Interrogating protein interaction networks through structural biology. Proc. Natl Acad. Sci. USA 99, 5896–5901 (2002).
Acknowledgements
We thank N. Eswar for preparing the histograms in Fig. 1, M. Simon, B. Jap and H. Noller for permission to use the structural images in Fig. 1, K. H. Downing for Fig. 2, B. Rockel for Fig. 3, and F. Alber for Figs 4 and 5a. We are also grateful to P. Bjorkman and H. Moss for commenting on the manuscript. This work has been supported in part by NIH grants (to A.S., R.M.G. and T.E.), the Agouron Institute (T.E.) and a Max-Planck Research Award (W.B.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sali, A., Glaeser, R., Earnest, T. et al. From words to literature in structural proteomics. Nature 422, 216–225 (2003). https://doi.org/10.1038/nature01513
Issue Date:
DOI: https://doi.org/10.1038/nature01513
This article is cited by
-
Functional interaction between S100A1 and MDM2 may modulate p53 signaling in normal and malignant endometrial cells
BMC Cancer (2022)
-
Protein complex prediction using Rosetta, AlphaFold, and mass spectrometry covalent labeling
Nature Communications (2022)
-
A simulated annealing approach for resolution guided homogeneous cryo‐electron microscopy image selection
Quantitative Biology (2020)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.