Inferring protein function from structure.
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Amino Acid Sequence↗
Biomedical subjects
Annabel E Todd
Publications and source records attributed to Annabel E Todd.
Plasticity of enzyme active sites.
The expectation is that any similarity in reaction chemistry shared by enzyme homologues is mediated by common functional groups conserved through evolution. However, detailed enzyme studies have revealed the flexibility of many active sites, in that different functional groups, unconserved with respect to position in the primary sequence, mediate the same mechanistic role. Nevertheless, the catalytic atoms might be spatially equivalent. More rarely, the active sites have completely different locations in the protein scaffold. This variability could result from: (1) the hopping of functional groups from one position to another to optimize catalysis; (2) the independent specialization of a low-activity primordial enzyme in different phylogenetic lineages; (3) functional convergence after evolutionary divergence; or (4) circular permutation events.
Amino Acid Sequence↗
Sequence and structural differences between enzyme and nonenzyme homologs.
To improve our understanding of the evolution of novel functions, we performed a sequence, structural, and functional analysis of homologous enzymes and nonenzymes of known three-dimensional structure. In most examples identified, the nonenzyme is derived from an ancestral catalytic precursor (as opposed to the reverse evolutionary scenario, nonenzyme to enzyme), and the active site pocket has been disrupted in some way, owing to the substitution of critical catalytic residues and/or steric interactions that impede substrate binding and catalysis. Pairwise sequence identity is typically insignificant, and almost one-half of the enzyme and nonenzyme pairs do not share any similarity in function. Heterooligomeric enzymes comprising homologous subunits in which one chain is catalytically inactive and enzyme polypeptides that contain internal catalytic and noncatalytic duplications of an ancient enzyme domain are also discussed.
Biopolymers↗
The CATH protein family database: a resource for structural and functional annotation of genomes.
Over the last decade, there have been huge increases in the numbers of protein sequences and structures determined. In parallel, many methods have been developed for recognising similarities between these proteins, arising from their common evolutionary background, and for clustering such relatives into protein families. Here we review some of the protein family resources available to the biologist and describe how these can be used to provide structural and functional annotations for newly determined sequences. In particular we describe recent developments to the CATH domain database of protein structural families which have facilitated genome annotation and which have also revealed important caveats that must be considered when transferring functional data between homologous proteins.
Databases, Protein↗
Target selection and determination of function in structural genomics.
The first crucial step in any structural genomics project is the selection and prioritization of target proteins for structure determination. There may be a number of selection criteria to be satisfied, including that the proteins have novel folds, that they be representatives of large families for which no structure is known, and so on. The better the selection at this stage, the greater is the value of the structures obtained at the end of the experimental process. This value can be further enhanced once the protein structures have been solved if the functions of the given proteins can also be determined. Here we describe the methods used at either end of the experimental process: firstly, sensitive sequence comparison techniques for selecting a high-quality list of target proteins, and secondly the various computational methods that can be applied to the eventual 3D structures to determine the most likely biochemical function of the proteins in question.
Amino Acid Motifs↗