UCSF

Every signaling event in biology begins with a molecular recognition process. In order for information to directly pass between two molecules, they must come in contact with each other for the requisite time to convey a given message. Specialized pathways often involve cascades of high fidelity interactions, near deterministically arriving at the same outcome for a given input. Other signals are capable of exerting disparate effects depending on the cellular context. Promiscuity in molecular recognition plays a central role in the capacity to produce different responses to the same signal.

For the steroid hormone receptors, the input signal is a small molecule ligand. Upon binding of the hormone, these molecules move to the nucleus, localize to different genomic response elements, and regulate the transcription levels of many different genes by recruitment of transcriptional machinery. The abilities to recognize multiple DNA sequences and to recruit different coregulators require that these interaction surfaces adapt to and engage with diverse structures over a relatively narrow spectrum of interaction energies.

The essential functions of DNA recognition and coregulator binding were investigated using dynamic structural analyses and biophysical measurements of interaction energies. For both, the manifestations of structural remodeling and energetic perturbation at sites removed from the interaction surfaces serve as evidence for allosteric regulation. In DNA recognition, we learn that nucleotide sequence modulates the structure of the dimerization surface of the glucocorticoid receptor, affecting both the cooperativity of complex formation and the kinetics of dissociation. In coregulator binding to the androgen receptor, we find distant structural remodeling and energetic coupling to a site of post translational modification. Together, these allosteric mechanisms help explain functional discrimination in a background of energetic degeneracy.