Genomics structural

Related to the discipline of proteomics is that of structural genomics. The latter focuses upon the large-scale systematic study of gene product structure. While this embraces rRNA and tRNA, 

Until quite recently, X-ray crystallography was the technique used almost exclusively to resolve the 3-D structure of proteins. As well as itself being technically challenging, a major limitation of X-ray crystallography is the requirement for the target protein in crystalline form. It has thus far proved difficult or impossible to induce the majority of proteins to crystallize. Nuclear magnetic resonance (NMR) is an analytical technique which can also be used to determine the three-dimensional structure of a molecule without the necessity for crystallization. For many years, even the most powerful NMR machines could resolve the 3-D structure of only relatively small proteins (less than 20-25 kDa). However, recent analytical advances now render it possible to successfully analyse much larger proteins by this technique. 

The ultimate goal of structural genomics is to provide a complete 3-D description of any gene product. Also, as the structures of more and more proteins of known function are elucidated, it should become increasingly possible to link specific functional attributes to specific structural attributes. As such, it may prove ultimately feasible to predict protein function if its structure is known, and vice versa. 

Tlie stracture reveals tlie organization of the protein, RNA or complex in three dimensions, and thus allows the identification of die partial stmctures, domains, sequences and 

Tlie production of biological molecules, in particular proteins, for stmctural analysis is a major challenge primarily met by cloning and by purification. 

Automation will be a major key for the success of stmctural genomics. The development of effective macromolecular stmcture detemiination facilities using intense X-rays from synchroton sources and advances in protein expression, purification and crystallization are accelerating the process of determining the structures of target niacroniol-ecules.t  

Crystal Data collection - Diffraction images Measure X-ray diffraction intensities from a crystal 

Images Data processing - Intensities Calculate magnitude and errors of intensities Reduce the data to the proper symmetry group 

The structure reveals the organization of the protein, RNA or complex in three dimensions, and thus allows the identification of the partial structures, domains, sequences and interactions that determine the function(s) of the molecule. Protein-ligand complexes are especially useful providers of functional information as they define the location of the ligand, the active site, the conformational effects and the mechanism of action of the mol-ecule.  

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SK Burley, SC Almo, JB Bonano, M Capel, MR Chance, T Gaasterland, D Lm, A Sail, EW Studier, S Swammathan. Structural genomics Beyond the human genome project. Nat Genet 23 151-157, 1999. 

The increased speed of structure determination necessary for the structural genomics projects makes an independent validation of the structures (by comparison to expected properties) particularly important. Structure validation helps to correct obvious errors (e.g. in the covalent structure) and leads to a more standardised representation of structural data, e.g. by agreeing on a common atom name nomenclature. The knowledge of the structure quality is a prerequisite for further use of the structure, e.g. in molecular modelling or drug design. 

Structural genomics is the systematic effort to gain a complete structural description of a defined set of molecules, ultimately for an organism s entire proteome. Structural genomics projects apply X-ray crystallography and NMR spectroscopy in a high-throughput manner. 

The constantly increasing amount of data coming from high throughput experimental methods, from genome sequences, from functional- and structural genomics has given a rise to a need for computer-assisted methods to elucidate sequence-structure-function relationships. 

From the human genome project it is known, that roughly 30,000 proteins exist in humans. Currently only the 3D-structures of few thousand human pr oteins or protein domains are known. Structures of membrane-bound proteins are several magnitudes rarer. Beside efforts to solve further structures like structural genomics, there is a challenge for computational approaches to predict structures and function for homologous proteins. 

Structural genomics aims to use high-throughput structure determination and computational analysis to provide structures and/or 3D-models of every tractable protein. The intention is to determine as many protein structures as possible and to exploit the solved structures for the assignment of biological function to hypothetical proteins. 

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