Protein structure families

FIGURE 2 A one-dimensional NMR spectrum of a globin from a marine blood worm. This protein and sperm whale myoglobin are very close structural analogs, belonging to the same protein structural family and sharing an oxygen-transport function. 

I. Holm, CL Duzounis, S. Sander, G. Tuparev, and G. Vriend, A database of protein structure families with common folding motifs. Protein ScL 7 691-1696 (1992). 

A. S. Yang, B. Honig. An integrated approach to the analysis and modeling of protein sequences and structures. III. A comparative study of sequence conservation in protein structural families using multiple structural alignments. J Mol Biol. 2000, 301, 691-711. 

In this first part we introduce the notion of interaction network of amino adds of a protein (SSE-IN) and study some of the properties of these networks. We give different means to describe a protein structural family by characterizing their SSE-IN. Some of the properties. 

Database of Protein Structure Families with Common Folding Motifs. 

Ithough knowledge-based potentials are most popular, it is also possible to use other types potential function. Some of these are more firmly rooted in the fundamental physics of iteratomic interactions whereas others do not necessarily have any physical interpretation all but are able to discriminate the correct fold from decoy structures. These decoy ructures are generated so as to satisfy the basic principles of protein structure such as a ose-packed, hydrophobic core [Park and Levitt 1996]. The fold library is also clearly nportant in threading. For practical purposes the library should obviously not be too irge, but it should be as representative of the different protein folds as possible. To erive a fold database one would typically first use a relatively fast sequence comparison lethod in conjunction with cluster analysis to identify families of homologues, which are ssumed to have the same fold. A sequence identity threshold of about 30% is commonly... 

Holm L and C Sander 1994. The FSSP Database of Structurally Aligned Protein Fold Families. Ni Acids Research 22 3600-3609. 

Figure 1 The basis of comparative protein structure modeling. Comparative modeling is possible because evolution resulted in families of proteins, such as the flavodoxin family, modeled here, which share both similar sequences and 3D structures. In this illustration, the 3D structure of the flavodoxin sequence from C. crispus (target) can be modeled using other structures in the same family (templates). The tree shows the sequence similarity (percent sequence identity) and structural similarity (the percentage of the atoms that superpose within 3.8 A of each other and the RMS difference between them) among the members of the family.

Eortunately, a 3D model does not have to be absolutely perfect to be helpful in biology, as demonstrated by the applications listed above. However, the type of question that can be addressed with a particular model does depend on the model s accuracy. At the low end of the accuracy spectrum, there are models that are based on less than 25% sequence identity and have sometimes less than 50% of their atoms within 3.5 A of their correct positions. However, such models still have the correct fold, and even knowing only the fold of a protein is frequently sufficient to predict its approximate biochemical function. More specifically, only nine out of 80 fold families known in 1994 contained proteins (domains) that were not in the same functional class, although 32% of all protein structures belonged to one of the nine superfolds [229]. Models in this low range of accuracy combined with model evaluation can be used for confirming or rejecting a match between remotely related proteins [9,58]. 

Detailed protein structures have been reported for BPI and CETP. Given the aforementioned similarities within this gene family, these protein structures serve as a likely model for the protein structure of PLTP. CETP and BPI are elongated molecules, shaped like a boomerang. There are two domains with similar folds, and a central beta-sheet domain between these two domains. The molecules contain two lipid-binding sites, one in each domain near the interface of the barrels and the central beta-sheet. 

The abundance of structural information has led to a significant increase in the use of structure-based methods both to identify and to optimise inhibitors of protein kinases. The focus to date has centred upon small molecule ATP-competitive inhibitors and there are numerous examples of protein-ligand complexes available to guide design strategies. ATP binds in the cleft formed between the N- and C-terminal lobes of the protein kinase, forming several key interactions conserved across the protein kinase family. The adenine moiety lies in a hydrophobic region between the jS-sheet structure of subdomains I and II and residues from subdomains V and VIb. A... 

Prosite is perhaps the best known of the domain databases (Hofmann et al., 1999). The Prosite database is a good source of high quality annotation for protein domain families. Prosite documentation includes a section on the functional meaning of a match to the entry and a list of example members of the family. Prosite documentation also includes literature references and cross links to other databases such as the PDB collection of protein structures (Bernstein et al., 1977). For each Prosite document, there is a Prosite pattern, profile, or both to detect the domain family. The profiles are the most sensitive detection method in Prosite. The Prosite profiles provide Zscores for matches allowing statistical evaluation of the match to a new protein. Profiles are now available for many of the common protein domains. Prosite profiles use the generalized profile software (Bucher et al., 1996). 

The use of sequence information to frame structural, functional, and evolutionary hypotheses represents a major challenge for the postgeno-mic era. Central to an understanding of the evolution of sequence families is the concept of the domain a structurally conserved, genetically mobile unit. When viewed at the three-dimensional level of protein structure, a domain is a compact arrangement of secondary structures connected by linker polypeptides. It usually folds independently and possesses a relatively hydrophobic core (Janin and Chothia, 1985). The importance of domains is that they cannot be divided into smaller units— they represent a fundamental building block that can be used to understand the evolution of proteins. 

Experience gained from protein structure determination in the past 30 years demonstrates that domains possessing similar sequences also possess similar folds, leading to the inference that such domains are members of homologous families (Doolittle, 1995 Henikoff etal., 1997). Some homologous domain sequences have diverged considerably beyond the level at which homology can be reliably predicted. However,... 

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