Structural Genomics
Crystallography is unable to solve a large percentage
of protein structures anytime soon.
Structural genomics is an initiative to solve a large
percentage by
homology modeling.
There are 9 NIH-funded structural genomics centers/consortia in the USA, plus
commercial efforts and centers in other countries, for a total of >20
(>70 institutions).
Structural Genomics
- Identify sequence families for which no empirical template
exists for homology modeling.
- Choose some members of each family as "targets".
- The Protein Data Bank maintains a
target registry.
- In February, 2004, nearly 50,000 targets
were registered (75% in the previous year: Graph).
- Solve a target from each family by high-throughput crystallography,
providing a new template.
- This is the
bottleneck (Graph).
- Infer function from similar structures of known function, to be
confirmed biochemically (Zhang & Kim).
- Homology model all members of each family, using the new templates.
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By one estimate (Vitkup et al.), obtaining templates for 90% of proteins would
require solving
16,000 new sequence-unrelated structures. This is about three
times the world output of crystallography to date.
About 3% of this goal has been attained.
by
Eric Martz, University of Massachusetts, July 2003 (updated February 2004)
Further reading:
- The
Protein Data Bank's Structural Genomics Page
and
Target Registry.
- Success rates in crystallography.
- SPAM: Systematic Protein
Annotation and Modeling, a multi-institutional initiative to
provide tools to assist in selecting and registering targets for
structural genomics and for associating structure with function.
- structuralgenomics.org
Most recent first:
-
The Status of Structural Genomics through the analysis of current
targets and structures.
P. E. Bourne et al.,
Pacific Symposium on Biocomputing, R.B. Altman et al., eds.
World Scientific Publishing, Singapore, 404-416, 2004.
- Overview
of structural genomics: from structure to function,
Zhang & Kim, Curr. Opin. Chem. Biol. 7:28, 2003.
"These new structures have revealed many unexpected
functional and evolution relationships that were hidden at the
sequence level."
- Structural
genomics: current progress, Gerstein et al.,
Science 299:1663, 2003.
The authors make the point that overall
progress is much larger than the number of solved structures, since each
solution serves as a template for homology modeling a large family of
sequences. Also, work is often stopped on a target when a sequence-related
target is solved; hence not all uncompleted targets are "failures".
- Structural
genomics. Tapping DNA for structures produces a trickle,
Service, Science 298:948, 2002.
- Global
efforts in structural genomics, Stevens, Yokoyama & Wilson,
Science 294:89, 2001.
-
Completeness in structural genomics, Vitkup, Melamud, Moult & Sander,
Nature Structural Biology 8:559, 2001.
-
Structural genomics takes off, Thornton,
Trends Biochem. Sci., 26:88, 2001.