No abstract

Aromatic pollutants in the environments pose significant threat to human health due to their persistence and toxicity. Here, we report the design and comprehensive characterization of a set of aromatic biosensors constructed using green fluorescence protein as the reporter and aromatics-responsive transcriptional regulators, namely, NahR, XylS, HbpR, and DmpR, as the detectors. The genetic connections between the detectors and the reporter were carefully adjusted to achieve fold inductions far exceeding those reported in previous studies. For each biosensor, the functional characteristics including the dose-responses, dynamic range, and the detection spectrum of aromatic species were thoroughly measured. In particular, the interferences that nontypical inducers exert on each biosensor's response to its strongest inducer were evaluated. These well-characterized biosensors might serve as potent tools for environmental monitoring as well as quantitative gene regulation.

No abstract

Efforts to improve estrogen receptor-α (ER)–targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, noncanonical structural perturbations of the receptor ligand-binding domain (LBD) to antagonize proliferation in ER-positive breast cancer cells and in allele-specific resistance models. Our structural analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access nonconsensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity.