Local comparison of protein structures highlights cases of convergent evolution in analogous functional sites

We performed an exhaustive search for local structural similarities in an ensemble of non-redundant protein functional sites. With the purpose of finding new examples of convergent evolution, we selected only those matching sites composed of structural regions whose residue order is inverted in the relative protein sequences

Structure- and context-based analysis of the GxGYxYP family reveals a new putative class of glycoside hydrolase.

BackgroundGut microbiome metagenomics has revealed many protein families and domains found largely or exclusively in that environment. Proteins containing the GxGYxYP domain are over-represented in the gut microbiota, and are found in Polysaccharide Utilization Loci in the gut symbiont Bacteroides thetaiotaomicron, suggesting their involvement in polysaccharide metabolism, but little else is known of the function of this domain.ResultsGenomic context and domain architecture analyses support a role for the GxGYxYP domain in carbohydrate metabolism. Sparse occurrences in eukaryotes are the result of lateral gene transfer. The structure of the GxGYxYP domain-containing protein encoded by the BT2193 locus reveals two structural domains, the first composed of three divergent repeats with no recognisable homology to previously solved structures, the second a more familiar seven-stranded β/α barrel. Structure-based analyses including conservation mapping localise a presumed functional site to a cleft between the two domains of BT2193. Matching to a catalytic site template from a GH9 cellulase and other analyses point to a putative catalytic triad composed of Glu272, Asp331 and Asp333.ConclusionsWe suggest that GxGYxYP-containing proteins constitute a novel glycoside hydrolase family of as yet unknown specificity

Structural motifs recurring in different folds recognize the same ligand fragments

<p>Abstract</p> <p>Background</p> <p>The structural analysis of protein ligand binding sites can provide information relevant for assigning functions to unknown proteins, to guide the drug discovery process and to infer relations among distant protein folds. Previous approaches to the comparative analysis of binding pockets have usually been focused either on the ligand or the protein component. Even though several useful observations have been made with these approaches they both have limitations. In the former case the analysis is restricted to binding pockets interacting with similar ligands, while in the latter it is difficult to systematically check whether the observed structural similarities have a functional significance.</p> <p>Results</p> <p>Here we propose a novel methodology that takes into account the structure of both the binding pocket and the ligand. We first look for local similarities in a set of binding pockets and then check whether the bound ligands, even if completely different, share a common fragment that can account for the presence of the structural motif. Thanks to this method we can identify structural motifs whose functional significance is explained by the presence of shared features in the interacting ligands.</p> <p>Conclusion</p> <p>The application of this method to a large dataset of binding pockets allows the identification of recurring protein motifs that bind specific ligand fragments, even in the context of molecules with a different overall structure. In addition some of these motifs are present in a high number of evolutionarily unrelated proteins.</p

Development of a sequence based method for the prediction of protein function

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