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Structural genomics is a new and rapidly developing field in biology.
The goal of this field is to discover and analyze the structures of
all protein molecules in nature in order to provide a foundation for a
fundamental understanding of biology. Consortium researchers have
been leaders in the national and international effort to develop ideas
for this field and to engage the worldwide biological community in
discussing and advancing the field. Structural genomics is closely
tied to functional genomics, the identification of functions of all
proteins in nature, and to genomic sequencing, the determination of
the genetic blueprints of all organisms. Together these fields will
revolutionize biology over the next two decades.
This project will develop and demonstrate the power of structural
genomics--the determination and analysis of protein structure on a
genomic scale. We will determine the structures of over 400 proteins
from M. tuberculosis, and analyze these structures in the context of
functional information that currently exists and that we generate.
These structures will include about 40 novel folds and 200 new
families of protein structures. The database of linked structural and
functional information that we construct will form a lasting basis for
understanding M. tuberculosis pathogenesis and for structure-based
drug design.
To accomplish this we will develop scaleable
technologies that will make structural genomics feasible. Further, we
will demonstrate a Consortium approach to structural genomics that
allows a world-wide effort to be devoted to a defined set of
structural targets.
The TB Structural Genomics Consortium consists of
laboratories from institutions in countries. Consortium
laboratories are collectively responsible for of all protein
structures in the Protein Data Bank and have extensive records of
methods development. Consortium members have carried out a pilot
project on the structural genomics of a hyperthermophile that has
identified bottlenecks and resulted in development of methodologies
for high-throughput structure determination and analysis. The Consortium will have
centralized facilities that will carry out an increasing
fraction of routine tasks such as protein production, crystallization and X-ray data
collection. The structural and functional information obtained will be publically available.
By targeting functionally important proteins
through the use of genetic screens and genome-scale functional
assignments. We will use our green fluorescent protein-based
screening system to optimize proteins for expression, solubility and
methionine content. Crystallization will be carried out by a low-cost
system that combines automation of our stochastic screening protocol
with image analysis of droplets. We will emphasize selenomethionine
MAD X-ray data collection on characterized crystals at synchrotron
facilities, with concurrent structure solution using automated
software. Synchrotron time sufficient for collection of 300 MAD
structures per year has been secured for this program. Structural
data will be systematically analyzed for fold assignment, similarity
to other proteins, and local motifs. Analysis of structures
determined will use new function prediction methods that will guide
biochemical tests of function.