Transmission of light signals from the light-oxygen-voltage core via the hydrophobic region of the β-sheet surface in aureochrome-1

Light-Oxygen-Voltage (LOV) domains are responsible for detecting blue light (BL) and regulating the activities of effector domains in various organisms. Photozipper (PZ), an N-terminally truncated aureochrome-1 protein, contains a LOV domain and a basic leucin zipper (bZIP) domain and plays a role as a light-activatable transcription factor. PZ is monomeric in the dark state and undergoes non-covalent dimerization upon illumination with BL, subsequently increasing its affinity for the target DNA. To clarify the molecular mechanism of aureochromes, we prepared site-directed mutants of PZ and performed quantitative analyses in the dark and light states. Although the amino acid substitutions in the hinge region between the LOV core and A’α helix had minor effects on the dimerization and DNA-binding properties of PZ, the substitutions in the β-sheet region of the LOV core and in the A’α helix significantly affected these properties. We found that light signals are transmitted from the LOV core to the effector bZIP domain via the hydrophobic residues on the β-sheet. The light-induced conformational change possibly deforms the hydrophobic regions of the LOV core and induces the detachment of the A’α helix to expose the dimerization surface, likely activating the bZIP domain in a light-dependent manner.

EGFR Oncogenes Expressed In Glioblastoma Are Activated As Covalent Dimers And Paradoxically Stimulated By Erlotinib

Mutation of both the intracellular catalytic domain and the extracellular domain of the receptor for epidermal growth factor (EGFR) can drive oncogenicity. Despite clinical success with targeting EGFR catalytic site mutations, no drugs have proven effective in patients expressing allosteric extracellular domain EGFR mutations, including glioblastomas (GBM) where these mutations are highly expressed. We define the molecular mechanism for oncogenic activation of families of extracellular EGFR mutations and reveal how this mechanism renders current generation small molecule ATP-site inhibitors ineffective. We demonstrate that a group of commonly expressed extracellular domain EGFR mutants expressed in GBM is activated by disulfide-bond mediated covalent dimerization, collectively referred to as locked dimerization (LoDi) EGFR oncogenes. Strikingly, small molecules binding to the active kinase conformation (Type I), but not those binding to the inactive kinase conformation (Type II), potently inhibit catalytic site mutants, but induce covalent dimerization and activate LoDi-EGFR oncogenes, manifesting in paradoxical acceleration of proliferation.SignificanceOur data demonstrate how the locked-dimer mechanism of EGFR oncogenesis has a profound impact on the activity of small molecule inhibitors. This provides a mechanistic understanding for the failure of current generation EGFR inhibitors to effectively treat LoDi-EGFR mutants in GBM, and sets guidelines for discovery of selective LoDi-EGFR inhibitors.

Periodicity in Structure, Bonding, and Reactivity for P-Block Complexes of a Geometry-Constraining Triamide Ligand

The use of pincer ligands to access non-VSEPR geometries at main-group centers is an emerging strategy for eliciting new stoichiometric and catalytic reactivity. As part of this effort, several different tridentate trianionic substituents have to date been employed at a range of different central elements, providing a patchwork dataset that precludes rigorous structure-function correlation. Here we report an analysis of periodic trends in structure (solid, solution, and gas phase), bonding, and reactivity based on systematic variation of the central element (P, As, Sb, or Bi) with retention of a single tridentate triamide substituent. In this homologous series, the central element can adopt either a bent or planar geometry. The tendency to adopt planar geometries increases descending the group with the phosphorus triamide (<b>1</b>) and its arsenic congener (<b>2</b>) exhibiting bent conformations, and the antimony (<b>3</b>) and bismuth (<b>4</b>) analogues exhibiting a predominantly planar structure in solution. This trend has been rationalized using the energy decomposition analysis. A rare phase-dependent dynamic covalent dimerization was observed for <b>3</b> and the associated thermodynamic parameters were established quantitatively. Planar geometries were found to engender lower LUMO energies and smaller band gaps as compared to bent ones, resulting in different reactivity patterns. These results provide a benchmark dataset to guide further research in this rapidly emerging area.

Periodicity in Structure, Bonding, and Reactivity for P-Block Complexes of a Geometry-Constraining Triamide Ligand

The use of pincer ligands to access non-VSEPR geometries at main-group centers is an emerging strategy for eliciting new stoichiometric and catalytic reactivity. As part of this effort, several different tridentate trianionic substituents have to date been employed at a range of different central elements, providing a patchwork dataset that precludes rigorous structure-function correlation. Here we report an analysis of periodic trends in structure (solid, solution, and gas phase), bonding, and reactivity based on systematic variation of the central element (P, As, Sb, or Bi) with retention of a single tridentate triamide substituent. In this homologous series, the central element can adopt either a bent or planar geometry. The tendency to adopt planar geometries increases descending the group with the phosphorus triamide (<b>1</b>) and its arsenic congener (<b>2</b>) exhibiting bent conformations, and the antimony (<b>3</b>) and bismuth (<b>4</b>) analogues exhibiting a predominantly planar structure in solution. This trend has been rationalized using the energy decomposition analysis. A rare phase-dependent dynamic covalent dimerization was observed for <b>3</b> and the associated thermodynamic parameters were established quantitatively. Planar geometries were found to engender lower LUMO energies and smaller band gaps as compared to bent ones, resulting in different reactivity patterns. These results provide a benchmark dataset to guide further research in this rapidly emerging area.

Room-temperature surface-assisted reactivity of a melanin precursor: silver metal–organic coordination versus covalent dimerization on gold

The surface drives the self-assembly of a catechol–indole molecule, triggering metal–organic coordination on silver and dimerization on gold at room temperature.