title: Using orthologous and paralogous proteins to identify specificity determining residues.
abstract: BACKGROUND
  Concepts of orthology and paralogy are become increasingly important as whole-genome comparison allows their identification in complete genomes. Functional specificity of proteins is assumed to be conserved among orthologs and is different among paralogs. We used this assumption to identify residues which determine specificity of protein-DNA and protein-ligand recognition. Finding such residues is crucial for understanding mechanisms of molecular recognition and for rational protein and drug design.
  
  
  RESULTS
  Assuming conservation of specificity among orthologs and different specificity of paralogs, we identify residues which correlate with this grouping by specificity. The method is taking advantage of complete genomes to find multiple orthologs and paralogs. The central part of this method is a procedure to compute statistical significance of the predictions. The procedure is based on a simple statistical model of protein evolution. When applied to a large family of bacterial transcription factors, our method identified 12 residues that are presumed to determine the protein-DNA and protein-ligand recognition specificity. Structural analysis of the proteins and available experimental results strongly support our predictions. Our results suggest new experiments aimed at rational re-design of specificity in bacterial transcription factors by a minimal number of mutations.
  
  
  CONCLUSIONS
  While sets of orthologous and paralogous proteins can be easily derived from complete genomic sequences, our method can identify putative specificity determinants in such proteins.
authors.affiliation: Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, 77 Massachusetts ave, Cambridge, MA 02139. leonid@mit.edu
authors.forename: Leonid A
authors.initials: LA
authors.lastname: Mirny
authors.forename: Mikhail S
authors.initials: MS
authors.lastname: Gelfand
mesh_terms: D000596:Amino Acids / Q000502:physiology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000502:physiology; D019295:Computational Biology / Q000379:methods; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology; D030562:Databases, Protein; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000502:physiology*; D016680:Genome, Bacterial; D056968:Lac Repressors; D012097:Repressor Proteins / Q000737:chemistry / Q000502:physiology; D017386:Sequence Homology, Amino Acid
chemical_list: D000596:Amino Acids; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; C539064:LacI protein, E coli; C065825:PurR protein, Bacteria; C489317:PurR protein, E coli; D012097:Repressor Proteins