Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation.

Class B G protein-coupled receptors (GPCRs) are important therapeutic targets for major diseases. Here, we present structures of peptide and Gs-bound pituitary adenylate cyclase-activating peptide, PAC1 receptor, and corticotropin-releasing factor (CRF), (CRF1) receptor. Together with recently solved structures, these provide coverage of the major class B GPCR subfamilies. Diverse orientations of the extracellular domain to the receptor core in different receptors are at least partially dependent on evolutionary conservation in the structure and nature of peptide interactions. Differences in peptide interactions to the receptor core also influence the interlinked TM2-TM1-TM6/ECL3/TM7 domain, and this is likely important in their diverse signaling. However, common conformational reorganization of ECL2, linked to reorganization of ICL2, modulates G protein contacts. Comparison between receptors reveals ICL2 as a key domain forming dynamic G protein interactions in a receptor- and ligand-specific manner. This work advances our understanding of class B GPCR activation and Gs coupling.

Photomodulation of bacterial growth and biofilm formation using carbohydrate-based surfactants.

Naturally occurring and synthetic carbohydrate amphiphiles have emerged as a promising class of antimicrobial and antiadhesive agents that act through a number of dynamic and often poorly understood mechanisms. In this paper, we provide the first report on the application of azobenzene trans-cis photoisomerization for effecting spatial and temporal control over bacterial growth and biofilm formation using carbohydrate-based surfactants. Photocontrollable surface tension studies and small angle neutron scattering (SANS) revealed the diverse geometries and dimensions of self-assemblies (micelles) made possible through variation of the head group and UV-visible light irradiation. Using these light-addressable amphiphiles, we demonstrate optical control over the antibacterial activity and formation of biofilms against multi-drug resistant (MDR) Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative Escherichia coli. To probe the mechanism of bioactivity further, we evaluated the impact of trans-cis photoisomerization in these surfactants on bacterial motility and revealed photomodulated enhancement in swarming motility in P. aeruginosa. These light-responsive amphiphiles should attract significant interest as a new class of antibacterial agents and as investigational tools for probing the complex mechanisms underpinning bacterial adhesion and biofilm formation.