Michael C. Young

Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis

Significance The exocyst complex is a conserved protein complex that tethers the secretory vesicles to the site of membrane fusion during exocytosis, an essential cellular process that transports molecules, such as protein, to the cell surface or extracellular space. We identified a small molecule that targets the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex to inhibit exocytosis. This compound made it possible to control the dynamics of the exocytosis process in a dosage-dependent manner in different organisms and overcame the mutant lethality and genetic redundancy issues in studying mechanisms of exocyst complex regulation. Further design of molecules with higher affinity and more potent activity may make it possible to use drugs to control human diseases related to exocytosis, such as cancer and diabetes. The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. This study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.

A Supramolecular Sorting Hat: Stereocontrol in Metal–Ligand Self-Assembly by Complementary Hydrogen Bonding†

A combination of self-complementary hydrogen bonding and metal-ligand interactions allows stereocontrol in the self-assembly of prochiral ligand scaffolds. A unique, non-tetrahedral M4L6 structure is observed upon multicomponent self-assembly of 2,7-diaminofluorenol with 2-formylpyridine and Fe(ClO4)2. The stereochemical outcome of the assembly is controlled by self-complementary hydrogen bonding between both individual ligands and a suitably sized counterion as template. This hydrogen-bonding-mediated stereoselective metal-ligand assembly allows the controlled formation of nonsymmetric discrete cage structures from previously unexploited ligand scaffolds.

Narcissistic Self‐Sorting in Self‐Assembled Cages of Rare Earth Metals and Rigid Ligands

Highly selective, narcissistic self-sorting can be achieved in the formation of self-assembled cages of rare earth metals with multianionic salicylhydrazone ligands. The assembly process is highly sensitive to the length of the ligand and the coordination geometry. Most surprisingly, high-fidelity sorting is possible between ligands of identical coordination angle and geometry, differing only in a single functional group on the ligand core, which is not involved in the coordination. Supramolecular effects allow discrimination between pendant functions as similar as carbonyl or methylene groups in a complex assembly process.

Cooperative thermodynamic control of selectivity in the self-assembly of rare earth metal-ligand helices.

Metal-selective self-assembly with rare-earth cations is possible with suitable rigid, symmetrical bis-tridentate ligands. Kinetically controlled formation is initially observed, with smaller cations preferentially incorporated. Over time, the more thermodynamically favorable complexes with larger metals are formed. This thermodynamic control is a cooperative supramolecular phenomenon and only occurs upon multiple-metal-based self-assembly: single-metal ML3 analogues do not show reversible selectivity. The selectivity is dependent on small variations in lanthanide ionic radius and occurs despite identical coordination-ligand coordination geometries and minor size differences in the rare-earth metals.

A Membrane‐Bound Synthetic Receptor that Promotes Growth of a Polymeric Coating at the Bilayer–Water Interface

Primed for action: Atom-transfer radical polymerization (ATRP) can be promoted at a bilayer-water interface by anchoring initiator molecules (see scheme; red) in a membrane-bound synthetic receptor (yellow). The bilayer is formed on a calcinated nanofilm (gray) on a gold surface.

Catalytic Coupling between Unactivated Aliphatic C–H Bonds and Alkynes via a Metal–Hydride Pathway

We report a Rh(I)-catalyzed site-selective coupling between ketone β-C(sp3)-H bonds and aliphatic alkynes using an in situ-installed directing group. Upon hydrogenation or hydration, various β-alkylation or β-aldol products of the ketones are obtained with broad functional group tolerance. Mechanistic investigations support the involvement of a Rh-H intermediate through oxidative addition of Rh(I) into the β-C-H bonds. Thus, to the best of our knowledge, this transformation represents the first example of catalytic couplings between unsaturated hydrocarbons and unactivated aliphatic C-H bonds via a metal-hydride pathway.

Protein recognition by a self-assembled deep cavitand monolayer on a gold substrate.

This paper details the first use of a self-folding deep cavitand on a gold surface. A sulfide-footed deep, self-folding cavitand has been synthesized, and its attachment to a cleaned gold surface studied by electrochemical and SPR methods. Complete monolayer formation is possible if the cavitand folding is templated by noncovalent binding of choline or by addition of space-filling thiols to cover any gaps in the cavitand adsorption layer. The cavitand is capable of binding trimethylammonium-tagged guests from an aqueous medium and can be deposited in 2 × 2 microarrays on the surface for characterization by SPR imaging techniques. When biotin-labeled guests are used, the cavitand:guest construct can recognize and immobilize streptavidin proteins from aqueous solution, acting as an effective supramolecular biosensor for monitoring protein recognition.