Dual Activation Modes Enable Bifunctional Catalysis of Aldol Reactions by Flexible Dihydrazides.

Hydrazides are known to catalyze reactions of α,β-unsaturated aldehydes via transient iminium formation. The iminium intermediate displays enhanced electrophilicity, which facilitates conjugate additions and cycloadditions. We observed that a hydrazide embedded in a seven-membered ring catalyzes homoaldol condensation of a simple aldehyde in a process that displays an approximate second-order dependence on the hydrazide.

A New Mechanism for Formation of Glycine from Glyoxylic Acid: the Aza-Cannizzaro Reaction.

Glyoxylic acid and glycine are widely considered to have been important prebiotic building blocks. Several mechanistic routes have been previously examined for conversion of glyoxylic acid to glycine. Here we provide evidence for a new mechanistic path.

Backbone Modification Provides a Long-Acting Inverse Agonist of Pathogenic, Constitutively Active PTH1R Variants.

Parathyroid hormone 1 receptor (PTH1R) plays a key role in mediating calcium homeostasis and bone development, and aberrant PTH1R activity underlies several human diseases. Peptidic PTH1R antagonists and inverse agonists have therapeutic potential in treating these diseases, but their poor pharmacokinetics and pharmacodynamics undermine their in vivo efficacy. Herein, we report the use of a backbone-modification strategy to design a peptidic PTH1R inhibitor that displays prolonged activity as an antagonist of wild-type PTH1R and an inverse agonist of the constitutively active PTH1R-H223R mutant both in vitro and in vivo.

Submillisecond Atomistic Molecular Dynamics Simulations Reveal Hydrogen Bond-Driven Diffusion of a Guest Peptide in Protein-RNA Condensate.

Liquid-liquid phase separation mediated by proteins and/or nucleic acids is believed to underlie the formation of many distinct condensed phases, or membraneless organelles, within living cells. These condensates have been proposed to orchestrate a variety of important processes. Despite recent advances, the interactions that regulate the dynamics of molecules within a condensate remain poorly understood.

Phosphorylation Sites of the Gastric Inhibitory Polypeptide Receptor (GIPR) Revealed by Trapped-Ion-Mobility Spectrometry Coupled to Time-of-Flight Mass Spectrometry (TIMS-TOF MS).

The gastric inhibitory polypeptide receptor (GIPR), a G protein-coupled receptor (GPCR) that regulates glucose metabolism and insulin secretion, is a target for the development of therapeutic agents to address type 2 diabetes and obesity. Signal transduction processes mediated by GPCR activation typically result in receptor phosphorylation, but very little is known about GIPR phosphorylation. Mass spectrometry (MS) is a powerful tool for detecting phosphorylation and other post-translational modifications of proteins and for identifying modification sites.