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By:
Vaibhav Kumar Maurya
Genomics is the molecular
characterization of whole
genomes.
It characterizes the physical nature of
whole genome.
It includes the genetic mapping, physical
mapping and sequencing of whole
genomes.
It describes the 3D structure of every
protein encoded by a given genome.
Structural genomics attempts to determine the structure of every protein encoded by the genome.
Traditional structure prediction focuses on one particular protein.
Economy of scale
Scientific community gets immediate access to new structure as well as to reagents such as clones & proteins.
Many of the structure of protein are of unknown function & don’t have corresponding publication.
It requires new ways of communicating the strinformation to the broader research community.
To identify novel protein folds:
Done by ab-initio modeling.
Protein 3D structure determination:
-3D structure knowledge is important to understand the function of protein.
-It is also used in drug discovery and protein engineering.
full structural coverage of a simple model organism
Structural genomics takes advantage of completed genome sequence in order to determine protein structure.
The gene sequence of the target protein can be compared to a known sequence & structure information can be inferred from known protein structure.
Structure genomics can be used to predict novel protein folds based on other structural data.
It also uses modeling based approach that relies on homology b/w the unknown protein & a solved protein.
Completed genome sequence allows every ORF to be cloned & expressed as protein.
The proteins are then purified and crystallised
Then subjected to str determination: X-ray crystallography & NMR
The whole genome sequence allows for the design of every primer required in order to amplify all the ORFs, clone into bacteria and express them
This whole genome approach allows for structure determination of every protein that is encoded by the genome.
1. AB-INITIO METHOD: This approach uses protein sequence data & the chemical & physical interaction of the encoded amino acid to predict 3D str of protein with no homology to solve protein structure.
Rosetta program: highly successful method
It divides protein into short segment and arranges short polypeptide chain into a low energy local conformation.
Available for commercial use and for non commercial use Robetta is used.
2. SEQUENCE BASED MODELING
This method compares the gene sequence of an unknown protein with sequence of protein with known structure.
Depending on degree of similarity b/w the sequence the str of known protein can be used as model for solving the str of unknown protein.
3. THREADING
It is based on fold similarities rather than sequence identity.
This method is used to identify distantly related protein & can be used to infer molecular functions.
1. Mycobacterium tuberculosis proteome
-The goal of the TB Structural Genomics Consortium is to determine the structures of potential drug targets in Mycobacterium tuberculosis, the bacterium that causes tuberculosis.
- The development of novel drug therapies against tuberculosis are particularly important given the growing problem of multi-drug-resistant tuberculosis.
2. The Thermotogo maritima proteome
One current goal of the Joint Center for Structural Genomics (JCSG), a part of the Protein Structure Initiative (PSI) is to solve the structures for all the proteins in Thermotogomaritima, a thermophilic bacteria.
- T. maritima was selected as a structural genomics target based on its relatively small genome consisting of 1,877 genes and the hypothesis that the proteins expressed by a thermophilicbacterium would be easier to crystallize.
Protein bank (PDB): repository for protein sequence and structural information
UniProt: provides sequence and functional information
Structural Classification of Proteins (SCOP Classifications): hierarchical-based approach
Class, Architecture, Topology and Homologous superfamily (CATH): hierarchical-based approach
The structural genomics experimental pipeline.
