title: Structural-based analysis of dihydrofolate reductase evolution.
abstract: The evolution of dihydrofolate reductase (DHFR) was studied through a comprehensive structural-based analysis. An amino acid sequence alignment was generated from a superposition of experimentally determined X-ray crystal structures of wild-type (wt) DHFR from the Protein Data Bank (PDB). Using this structure-based alignment of DHFR, a metric was generated for the degree of conservation at each alignment site - not only in terms of amino acid residue, but also secondary structure, and residue class. A phylogenetic tree was generated using the alignment that compared favorably with the canonical phylogeny. This structure-based alignment was used to confirm that the degree of conservation of active-site residues in terms of both sequence as well as structure was significantly greater than non-active site residues. These results can be used in helping to understand the likely future evolution of DHFR in response to novel therapies.
authors.affiliation: Southwestern College, 900 Otay Lakes Rd., Chula Vista, CA 91910, USA. dhecht@swccd.edu
authors.forename: David
authors.initials: D
authors.lastname: Hecht
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tran
authors.forename: Gary B
authors.initials: GB
authors.lastname: Fogel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D006801:Humans; D008958:Models, Molecular; D010802:Phylogeny; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000235:genetics*
chemical_list: D013762:Tetrahydrofolate Dehydrogenase