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. 2004 Oct;14(10B):2145-54.
doi: 10.1101/gr.2537904.

High-throughput computational and experimental techniques in structural genomics

Mark R Chance  1 , Andras Fiser, Andrej Sali, Ursula Pieper, Narayanan Eswar, Guiping Xu, J Eduardo Fajardo, Thirumuruhan Radhakannan, Nebojsa Marinkovic
Affiliations

High-throughput computational and experimental techniques in structural genomics

Mark R Chance et al. Genome Res. 2004 Oct.

Abstract

Structural genomics has as its goal the provision of structural information for all possible ORF sequences through a combination of experimental and computational approaches. The access to genome sequences and cloning resources from an ever-widening array of organisms is driving high-throughput structural studies by the New York Structural Genomics Research Consortium. In this report, we outline the progress of the Consortium in establishing its pipeline for structural genomics, and some of the experimental and bioinformatics efforts leading to structural annotation of proteins. The Consortium has established a pipeline for structural biology studies, automated modeling of ORF sequences using solved (template) structures, and a novel high-throughput approach (metallomics) to examining the metal binding to purified protein targets. The Consortium has so far produced 493 purified proteins from >1077 expression vectors. A total of 95 have resulted in crystal structures, and 81 are deposited in the Protein Data Bank (PDB). Comparative modeling of these structures has generated >40,000 structural models. We also initiated a high-throughput metal analysis of the purified proteins; this has determined that 10%-15% of the targets contain a stoichiometric structural or catalytic transition metal atom. The progress of the structural genomics centers in the U.S. and around the world suggests that the goal of providing useful structural information on most all ORF domains will be realized. This projected resource will provide structural biology information important to understanding the function of most proteins of the cell.

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Figures

Figure 1
Figure 1
The corrected fluorescence counts for each metal atom are shown in histogram format (i.e., sample well counts minus counts from a blank well). The corrected counts for nickel are very far above background. The inset shows electron orbitals in schematic form with incident X-ray, the transition from higher to lower energy orbitals, and emission of X-ray fluorescence illustrated. The incident X-ray (Eo) knocks out a 1s electron, the unstable core hole is filled by the subsequent transition (seen in color), and a fluorescent X-ray of energy characteristic for the metal atom is emitted (Ef).
Figure 2
Figure 2
Protein domains will be solved by structural genomics, the docking of domains in protein structures or the structures of assemblies will be a challenging next step for structural biology to be solved by a combination of structure modeling of domains combined with experimental data from techniques such as cryo-EM, cross-linking, footprinting, and genetic knockout analysis.
See this image and copyright information in PMC

References

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WEB SITE REFERENCES

    1. www.nigms.nih.gov/psi; NIH Web site providing information and relevant links for the Protein Structure Initiative.
    1. http://targetdb.pdb.org; Web site operated by the Protein Databank to allow searching of targets from the structural genomics centers.
    1. www.nysgxrc.org; Web site operated by the NYSGRC. Its functions are to provide a public target list and progress as well as to allow consortium members to enter target data.
    1. http://salilab.org/modbase; MODBASE, a comprehensive database of comparative protein structure models.
    1. www-archbac.u-psud.fr/genomics/COG_Guess.html; Clusters of Orthologous Groups Database Query Page to perform similarity search in COG database. This provides a function and COG category guess for input sequence.

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