The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumors; however, mutations at SMO have been found to abolish their anti-tumor effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6–2.8Å resolution. The long and narrow cavity in the transmembrane domain of SMO harbors multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D4736.55 elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules.

The use of digital echosounders with post-processing commercial seabed classification software is becoming increasingly popular to create high-resolution resource maps of marine habitats over large scales. Here, we examine the Biosonics Visual Bottom Typing (VBT) seabed classification software (version 1.91). Although the VBT software uses potentially robust seabed classification parameters and has many useful features, a major drawback of the software is that it does not normalize echoes to a reference depth (typically the average survey depth). Depth normalizing adjusts for a change in echo length with depth. Without it, the VBT classification parameters that are calculated from the energy integral of the returned echo envelope over a fixed sampling window can be depth biased. The degree of misclassification from depth biasing will depend on the particular echosounder specifications (beamwidth (at −3dB) and pulse length) and characteristics of the survey area (depth variation and bottom acoustic diversity). Depth normalization applied before classification parameters are calculated is a very simple solution to potential depth-related misclassification and should be incorporated into the VBT software as a matter of priority to ensure its reliability and broad user application.

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