Publications

Structural studies of caspase-1 reveal that the dimeric thiol protease can exist in two states: in an on-state, when the active site is occupied, or in an off-state, when the active site is empty or when the enzyme is bound by a synthetic allosteric ligand at the dimer interface approximately 15 A from the active site. A network of 21 hydrogen bonds from nine side chains connecting the active and allosteric sites change partners when going between the on-state and the off-state. Alanine-scanning mutagenesis of these nine side chains shows that only two of them-Arg286 and Glu390, which form a salt bridge-have major effects, causing 100- to 200-fold reductions in catalytic efficiency (k(cat)/K(m)). Two neighbors, Ser332 and Ser339, have minor effects, causing 4- to 7-fold reductions. A more detailed mutational analysis reveals that the enzyme is especially sensitive to substitutions of the salt bridge: even a homologous R286K substitution causes a 150-fold reduction in k(cat)/K(m). X-ray crystal structures of these variants suggest the importance of both the salt bridge interaction and the coordination of solvent water molecules near the allosteric binding pocket. Thus, only a small subset of side chains from the larger hydrogen bonding network is critical for activity. These form a contiguous set of interactions that run from one active site through the allosteric site at the dimer interface and onto the second active site. This subset constitutes a functional allosteric circuit or "hot wire" that promotes site-to-site coupling.

A key goal of pharmacogenetics--the use of genetic variation to elucidate inter-individual variation in drug treatment response--is to aid the development of predictive genetic tests that could maximize drug efficacy and minimize drug toxicity. The completion of the Human Genome Project and the associated HapMap Project, together with advances in technologies for investigating genetic variation, have greatly advanced the potential to develop such tests; however, many challenges remain. With the aim of helping to address some of these challenges, this article discusses the steps that are involved in the development of predictive tests for drug treatment response based on genetic variation, and factors that influence the development and performance of these tests.

OBJECTIVE

To conduct a meta-analytic review of HIV interventions for heterosexual African Americans to determine the overall efficacy in reducing HIV-risk sex behaviors and incident sexually transmitted diseases and identify intervention characteristics associated with efficacy.

METHODS

Comprehensive searches included electronic databases from 1988 to 2005, handsearches of journals, reference lists of articles, and contacts with researchers. Thirty-eight randomized controlled trials met the selection criteria. Random-effects models were used to aggregate data.

RESULTS

Interventions significantly reduced unprotected sex (odds ratio = 0.75; 95% confidence interval = 0.67, 0.84; 35 trials; N = 14 682) and marginally significantly decreased incident sexually transmitted diseases (odds ratio = 0.88; 95% confidence interval = 0.72, 1.07; 10 trials; N = 10 944). Intervention characteristics associated with efficacy include cultural tailoring, aiming to influence social norms in promoting safe sex behavior, utilizing peer education, providing skills training on correct use of condoms and communication skills needed for negotiating safer sex, and multiple sessions and opportunities to practice learned skills.

CONCLUSION

Interventions targeting heterosexual African Americans are efficacious in reducing HIV-risk sex behaviors. Efficacious intervention components identified in this study should be incorporated into the development of future interventions and further evaluated for effectiveness.