Protein structure databases

SCOP Structural Classification of Proteins. Hierarchical protein structure database... 

In the protein structure database PDB ( http //www. rcsb.org/pdb), by X-ray crystallography and NMR spectroscopy, experimentally solved 3D-protein structures are available to the public. Homology model building for a query sequence uses protein portions of known 3D-stmctures as structural templates for proteins with high sequence similarity. 

Due to the ready accessibility of SH2 domains by molecular biology techniques, numerous experimentally determined 3D structures of SH2 domains derived by X-ray crystallography as well as heteronuclear multidimensional NMR spectroscopy are known today. The current version of the protein structure database, accessible to the scientific community by, e.g., the Internet (http //www.rcsb.org/pdb/) contains around 80 entries of SH2 domain structures and complexes thereof. Today, the SH2 domain structures of Hck [62], Src [63-66], Abl [67], Grb2 [68-71], Syp [72], PLCy [73], Fyn [74], SAP [75], Lck [76,77], the C- and N-terminal SH2 domain ofp85a [78-80], and of the tandem SH2 domains Syk [81,82], ZAP70 [83,84], and SHP-2 [85] are determined. All SH2 domains display a conserved 3D structure as can be expected from multiple sequence alignments (Fig. 4). The common structural fold consists of a central three-stranded antiparallel ft sheet that is occasionally extended by one to three additional short strands (Fig. 5). This central ft sheet forms the spine of the domain which is flanked on both sides by regular a helices [49, 50,60]. 

Figure 2. Three-dimensional structure of human cytochrome c created by Protein Adviser, ver 3.0 (FQS, Hakata, Japan) with PDB file of human cytochrome c down-loaded from protein structure database of NCBI. a-Helices are shown as purple ribbons, random coils as white strands, and P-tums are blue (see separate colour tip). Heme c is depicted in white straight lines inside the protein.

Computation proteome annotation is the process of proteome database mining, which includes structure/fold prediction and functionality assignment. Methodologies of secondary structure prediction and problems of protein folding are discussed. Approaches to identify functional sites are presented. Protein structure databases are surveyed. Secondary structure predictions and pattern/fold recognition of proteins using the Internet resources are described. 

Comparing and overlapping two protein structures quantitatively remain an active area of development in structural biochemistry. Methods for protein comparison generally rely on a fast full search of protein structure database. Some of these methods that are available over the Internet are listed in Table 15.1. 

Atomic contacts that are not abundant in the protein structure database are good indicators of local model-building problems [63]. Atomic contacts are observed because they are energetically favored. Real structures cannot tolerate too many unfavorable interactions. Unis fora model to be correct, only a few infrequently observed atomic contacts are allowed. This quality control of local packing has proven to be the most powerful tool for the detection of abnormal structures. 

Evidence for domain recruitment has been identified in a wide variety of proteins [47], mechanistically ranging from simple N- or C-terminal fusion to multiple internal insertions and possibly circular permutations [48]. A recent analysis of proteins in the protein structure database (PDB) has further indicated that structural rearrangements as a result of domain shuffling have significantly contributed to today s functional diversity [49]. A brief overview of the various modes of domain recruitment and their effects on function, is presented on examples of /lex-barrel structures. 

The UniProt KB is an automatically and manually annotated protein database drawn from translation of DDBJ/EMBL-Bank/GenBank coding sequences and directly sequenced proteins. Each sequence receives a imique, stable identifier allowing unambiguous identification of any protein across datasets. The KB also provides cross-references to external data collections such as the underlying DNA sequence entries in the DDBJ/EMBL-Bank/GenBank nucleotide sequence databases, 2D PAGE and 3D protein structure databases, various protein domain... 

Molecular biology databases can be divided into groups, such as the sequences databases, which have actual DNA and protein sequence, sequence related databases, such as protein structure databases, whole species databases, metabolism databases and so forth. Figure 1.1 shows a representation of the main publicly available databases. The databases are represented as a network, with lines drawn between databases where a link has been defined between the databases. From this network it is possible to plot a path from a piece of data in one database, through to a related piece of data in another database. This link may sometimes be through the result of an application, which means that an application uses data from one database and produces some results which are included in the application result database and then linked to another database. 

One of the best known protein structure databases is the Protein Data Bank (PDB) [23]. PDB archives experimentally determined three-dimensional structures of biological macromolecules and contains atomic coordinates, bibliographic citations, primary and secondary structure information, as well as crystallographic structure factors and NMR experimental data... 

The X-ray crystal structure database led us to believe that peptide bonds adopt either the cis or trans conformation in native proteins [22,128]. However, NMR spectroscopy [143], and in a few cases, crystal structure analysis [144], provide encouraging experimental evidence of conformational peptide bond polymorphism of folded proteins. Furthermore, conformational changes in response to ligand binding, crystallization conditions and point mutations at remote sites are frequent. Consequently, the three-dimensional protein structure database contains homologous proteins that have different native conformations for a critical prolyl bond [12]. 

Figure 2 Position-specific rotamer distributions for Phe, His, and Tyr at the second and penultimate position in a short a-helix. It can be seen that only one rotamer is allowed at the C-terminal end, whereas the rotamer distribution is residue dependent at the N-terminal end of the helix. These rotamer distributions are obtained by searching the protein structure database for segments of residues that fulfill two criteria (1) the segment has a local backbone conformation similar to that of the fragment around the residue that has to be modeled, and (2) the database segment has the residue type at the middle position that has to be modeled.

Templates can be selected using the target sequence as a query for searching protein structure databases [e.g. Brookhaven Protein Data Bank (PDB) http / /www.rcsb.org/pdb/index.html Structural Classification of Proteins (SCOP) scop.mrc-lmb.cam.ac.uk/scop/ DALI www2.ebi.ac.uk/dali/ Class, Architecture, Topology and Homologous superfamily classification at CATH www.biochem.ucl.a-c.uk/bsm/cath/). 

As referred to in the previous section, the large body of information contained in the protein data bank, together with proprietary protein structure databases, is now enabling extremely comprehensive analyses of molecular interactions. In the 2011 volume of J. Med. Chem. Stahl et al. provide a superb overview of molecular interactions of importance to drug designers, which has been assembled through analysis of such databases. The quality of such scholarship can surely only enhance the design skills of those who study this compilation. 

Protein structural database approach to drug design... 

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