HOME

TheInfoList



OR:

Structural genomics seeks to describe the 3-dimensional structure of every protein encoded by a given
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
. This genome-based approach allows for a high-throughput method of structure determination by a combination of experimental and modeling approaches. The principal difference between structural genomics and traditional structural prediction is that structural genomics attempts to determine the structure of every protein encoded by the genome, rather than focusing on one particular protein. With full-genome sequences available, structure prediction can be done more quickly through a combination of experimental and modeling approaches, especially because the availability of large number of sequenced genomes and previously solved protein structures allows scientists to model protein structure on the structures of previously solved homologs. Because protein structure is closely linked with protein function, the structural genomics has the potential to inform knowledge of protein function. In addition to elucidating protein functions, structural genomics can be used to identify novel protein folds and potential targets for drug discovery. Structural genomics involves taking a large number of approaches to structure determination, including experimental methods using genomic sequences or modeling-based approaches based on sequence or
structural homology A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similari ...
to a protein of known structure or based on chemical and physical principles for a protein with no homology to any known structure. As opposed to traditional
structural biology Structural biology is a field that is many centuries old which, and as defined by the Journal of Structural Biology, deals with structural analysis of living material (formed, composed of, and/or maintained and refined by living cells) at every le ...
, the determination of a
protein structure Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, the monomers of the polymer. A single amino acid monomer ma ...
through a structural genomics effort often (but not always) comes before anything is known regarding the protein function. This raises new challenges in structural bioinformatics, i.e. determining protein function from its 3D structure. Structural genomics emphasizes high throughput determination of protein structures. This is performed in dedicated centers of structural genomics. While most structural biologists pursue structures of individual proteins or protein groups, specialists in structural genomics pursue structures of proteins on a genome wide scale. This implies large-scale cloning, expression and purification. One main advantage of this approach is economy of scale. On the other hand, the scientific value of some resultant structures is at times questioned. A ''Science'' article from January 2006 analyzes the structural genomics field. One advantage of structural genomics, such as the
Protein Structure Initiative The Protein Structure Initiative (PSI) was a USA based project that aimed at accelerating discovery in structural genomics and contribute to understanding biological function. Funded by the U.S. National Institute of General Medical Sciences (NIGMS ...
, is that the scientific community gets immediate access to new structures, as well as to reagents such as clones and protein. A disadvantage is that many of these structures are of proteins of unknown function and do not have corresponding publications. This requires new ways of communicating this structural information to the broader research community. The Bioinformatics core of the Joint center for structural genomics (JCSG) has recently developed a wiki-based approach namely
Open protein structure annotation network The Open Protein Structure Annotation Network (TOPSAN) is a wiki designed to collect, share and distribute information about protein three-dimensional structures The site runs on the MindTouch software. See also * Protein structure Protein st ...
(TOPSAN) for annotating protein structures emerging from high-throughput structural genomics centers.


Goals

One goal of structural genomics is to identify novel protein folds. Experimental methods of protein structure determination require proteins that express and/or crystallize well, which may inherently bias the kinds of proteins folds that this experimental data elucidate. A genomic, modeling-based approach such as ''ab initio'' modeling may be better able to identify novel protein folds than the experimental approaches because they are not limited by experimental constraints. Protein function depends on 3-D structure and these 3-D structures are more highly conserved than
sequences In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is called t ...
. Thus, the high-throughput structure determination methods of structural genomics have the potential to inform our understanding of protein functions. This also has potential implications for drug discovery and protein engineering. Furthermore, every protein that is added to the structural database increases the likelihood that the database will include homologous sequences of other unknown proteins. The
Protein Structure Initiative The Protein Structure Initiative (PSI) was a USA based project that aimed at accelerating discovery in structural genomics and contribute to understanding biological function. Funded by the U.S. National Institute of General Medical Sciences (NIGMS ...
(PSI) is a multifaceted effort funded by the
National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
with various academic and industrial partners that aims to increase knowledge of protein structure using a structural genomics approach and to improve structure-determination methodology.


Methods

Structural genomics takes advantage of completed genome sequences in several ways in order to determine protein structures. The gene sequence of the target protein can also be compared to a known sequence and structural information can then be inferred from the known protein's structure. Structural genomics can be used to predict novel protein folds based on other structural data. Structural genomics can also take modeling-based approach that relies on homology between the unknown protein and a solved protein structure.


''de novo'' methods

Completed genome sequences allow every
open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...
(ORF), the part of a gene that is likely to contain the sequence for the
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...
and protein, to be cloned and expressed as protein. These proteins are then purified and crystallized, and then subjected to one of two types of structure determination:
X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
and
nuclear magnetic resonance Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...
(NMR). The whole genome sequence allows for the design of every primer required in order to amplify all of the ORFs, clone them into bacteria, and then express them. By using a whole-genome approach to this traditional method of protein structure determination, all of the proteins encoded by the genome can be expressed at once. This approach allows for the structural determination of every protein that is encoded by the genome.


Modelling-based methods


''ab initio'' modeling

This approach uses protein sequence data and the chemical and physical interactions of the encoded amino acids to predict the 3-D structures of proteins with no homology to solved protein structures. One highly successful method for ''ab initio'' modeling is the
Rosetta Rosetta or Rashid (; ar, رشيد ' ; french: Rosette  ; cop, ϯⲣⲁϣⲓⲧ ''ti-Rashit'', Ancient Greek: Βολβιτίνη ''Bolbitinē'') is a port city of the Nile Delta, east of Alexandria, in Egypt's Beheira governorate. The Ro ...
program, which divides the protein into short segments and arranges short polypeptide chain into a low-energy local conformation. Rosetta is available for commercial use and for non-commercial use through its public program, Robetta.


Sequence-based modeling

This modeling technique compares the gene sequence of an unknown protein with sequences of proteins with known structures. Depending on the degree of similarity between the sequences, the structure of the known protein can be used as a model for solving the structure of the unknown protein. Highly accurate modeling is considered to require at least 50% amino acid sequence identity between the unknown protein and the solved structure. 30-50% sequence identity gives a model of intermediate-accuracy, and sequence identity below 30% gives low-accuracy models. It has been predicted that at least 16,000 protein structures will need to be determined in order for all structural motifs to be represented at least once and thus allowing the structure of any unknown protein to be solved accurately through modeling. One disadvantage of this method, however, is that structure is more conserved than sequence and thus sequence-based modeling may not be the most accurate way to predict protein structures.


Threading

Threading bases structural modeling on fold similarities rather than sequence identity. This method may help identify distantly related proteins and can be used to infer molecular functions.


Examples of structural genomics

There are currently a number of on-going efforts to solve the structures for every protein in a given proteome.


''Thermotogo maritima'' proteome

One current goal of the Joint Center for Structural Genomics (JCSG), a part of the
Protein Structure Initiative The Protein Structure Initiative (PSI) was a USA based project that aimed at accelerating discovery in structural genomics and contribute to understanding biological function. Funded by the U.S. National Institute of General Medical Sciences (NIGMS ...
(PSI) is to solve the structures for all the proteins in '' Thermotogo maritima'', a thermophillic bacterium. ''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 thermophilic bacterium would be easier to crystallize. Lesley ''et al'' used ''
Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' to express all the open-reading frames (ORFs) of ''T. martima''. These proteins were then crystallized and structures were determined for successfully crystallized proteins using X-ray crystallography. Among other structures, this structural genomics approach allowed for the determination of the structure of the TM0449 protein, which was found to exhibit a novel fold as it did not share structural homology with any known protein.


''Mycobacterium tuberculosis'' proteome

The goal of the
TB Structural Genomics Consortium TB or Tb may refer to: Science and technology Computing * Terabyte (TB), a unit of information (often measuring storage capacity) * Terabit (Tb), a unit of information (often measuring data transfer) * Thunderbolt (interface) * Test bench Vehicle ...
is to determine the structures of potential drug targets in ''
Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...
'', 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 Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampin. Some f ...
. The fully sequenced genome of ''M. tuberculosis'' has allowed scientists to clone many of these protein targets into expression vectors for purification and structure determination by X-ray crystallography. Studies have identified a number of target proteins for structure determination, including extracellular proteins that may be involved in pathogenesis, iron-regulatory proteins, current drug targets, and proteins predicted to have novel folds. So far, structures have been determined for 708 of the proteins encoded by ''M. tuberculosis''.


Protein structure databases and classifications

*
Protein Data Bank The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The data, typically obtained by X-ray crystallography, NMR spectroscopy, or, increasingly, cry ...
(PDB): repository for protein sequence and structural information *
UniProt UniProt is a freely accessible database of protein sequence and functional information, many entries being derived from genome sequencing projects. It contains a large amount of information about the biological function of proteins derived from ...
: provides sequence and functional information * Structural Classification of Proteins (SCOP Classifications): hierarchical-based approach * Class, Architecture, Topology and Homologous superfamily (CATH): hierarchical-based approach


See also

*
Genomics Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...
*
Omics The branches of science known informally as omics are various disciplines in biology whose names end in the suffix '' -omics'', such as genomics, proteomics, metabolomics, metagenomics, phenomics and transcriptomics. Omics aims at the collect ...
* Structural proteomics *
Protein Structure Initiative The Protein Structure Initiative (PSI) was a USA based project that aimed at accelerating discovery in structural genomics and contribute to understanding biological function. Funded by the U.S. National Institute of General Medical Sciences (NIGMS ...


References


Further reading

* * * * *


External links


Protein Structure Initiative (PSI)PSI Structural Biology Knowledgebase: A Nature Gateway
{{DEFAULTSORT:Structural Genomics Genomics Genome projects Structural biology Bioinformatics