Biomedical subjects

Thomas A Anderson

Publications and source records attributed to Thomas A Anderson.

3 recordsLinked to original sources

PubMed2005

Sequence determinants of a conformational switch in a protein structure.

The Arc repressor of bacteriophage P22 is a dimeric member of the ribbon-helix-helix family of transcription factors. Residues 9-14 of each wild-type Arc subunit pair to form two antiparallel beta-strands and have the alternating pattern of polar and nonpolar residues expected for a beta-ribbon with one solvent-exposed face and one face that forms part of the hydrophobic core. Simultaneously switching Asn-11 to Leu and Leu-12 to Asn changes the local binary sequence pattern to that of an amphipathic helix. Previous studies have shown that this double mutation results in replacement of the wild-type beta-ribbon by two right-handed 3(10)-helices. Moreover, an Arc variant bearing just the Asn-11 --> Leu mutation has an ambiguous binary pattern and can form either the ribbon or the helical structures, which interchange rapidly. Here, we study Arc mutants in which position 11 is occupied by Gly, Ala, Val, Ile, Leu, Met, Phe, or Tyr. These mutants adopt the wild-type beta-ribbon structure in a sequence context that stabilizes this fold, but they assume the alternative helical structure in a sequence background in which the wild-type fold is precluded by negative design. In an otherwise wild-type sequence background, the detailed chemical properties of the position 11 side chain dictate which of the two competing conformational folds is preferred.

Amino Acid Sequence↗

PubMed2003

Role of an N(cap) residue in determining the stability and operator-binding affinity of Arc repressor.

The Arc repressor of bacteriophage P22 is a member of the ribbon-helix-helix family of transcription factors. Ser32 is a solvent-exposed position that serves a structural role as the N(cap) residue of alpha-helix B of Arc, but also serves a functional role because its side chain is packed close to the sugar-phosphate DNA backbone in the repressor-operator complex. The tolerance of this N(cap) position to amino-acid substitutions was probed by determining the repressor activity in vivo, the thermal stability and the operator-binding activity in vitro of a set of 13 mutant proteins. The stability of position-32 Arc variants, except for Cys32, correlated well with the frequencies observed for the corresponding residues at N(cap) positions in alpha-helices of other proteins. Cysteine was quite stabilizing at the helix-B N(cap) position in Arc, but surprisingly was the least frequent N(cap) residue in the protein database. This latter finding may reflect a hyper-reactivity of N(cap) cysteines, which makes them prone to chemical modification. In general, only Arc variants with small, uncharged residues at position 32 were active in vivo or showed strong operator binding in vitro. Based upon the results presented here, revised sequence alignments of the MetJ and NikR subfamilies with Arc and other ribbon-helix-helix proteins are proposed.

Amino Acid Sequence↗

PubMed2003

Strategies to decrease costs of prescribing selective serotonin reuptake inhibitors at a VA Medical Center.

OBJECTIVE: The authors examined the efficacy of a multifaceted intervention designed to contain the cost of prescribing selective serotonin reuptake inhibitors (SSRIs) to inpatients and outpatients served by a Veterans Affairs (VA) medical center. METHODS: Elements of the intervention included identification of a preferred agent, tablet splitting, education and feedback for prescribers, and an electronic record and ordering system to facilitate changes in prescriber behaviors. VA databases were searched for information on use and costs of antidepressants. RESULTS: Over 35 months the number of patients treated with SSRIs and the amount spent on SSRIs increased. However, the mean monthly cost per patient decreased from $57.12 to $42.19. The projected cost savings over the 35 months was approximately $700,000; one-fourth of the savings was due to tablet splitting and three-fourths to changes in the proportions of the various SSRIs prescribed. A survey of the top 75 antidepressant prescribers showed that after the educational interventions, 91 percent were aware that citalopram was the medical center's preferred antidepressant, and 59 percent identified it as their own preferred first-line treatment. DISCUSSION AND CONCLUSIONS: The results suggest that multifaceted interventions can influence antidepressant costs through provider education and changes in pharmacy and computerized information processes, resulting in substantial cost savings for institutions.

Citalopram↗