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Compounds containing a primary amino group can protect against light-induced retinal degeneration in a mouse model of Stargardt’s disease and age-related retinal degeneration by forming a transient Schiff base with all-trans-retinal, lowering its intracellular concentration and preventing accumulation of lipofuscin chromophores in the eye.
Screens of large compound libraries identify new small–molecule proteostasis regulators that, by enhancing the activity of the heat shock response factor HSF–1 and by activating other components of the proteostasis network, such as the antioxidant response or the unfolded protein response pathways, restore protein folding in multiple models of protein conformational diseases.
Natural product–inspired compounds are primed to interact with and manipulate biological processes, but obtaining these complex molecules poses synthetic challenges. The development of a 12-step, 1-pot cascade reaction leads to the 'centrocountins', tetrahydroindoloquinolizines that modulate mitosis by targeting the centrosome-associated proteins nucleophosmin and Crm1.
The four subunits of the tetrameric voltage-sensitive HCN channel have different cAMP binding affinities, with the second and fourth binding events being positively cooperative and the third being negatively cooperative, suggesting a double-dimeric organization of the channel.
Threading of a polypeptide chain is required for knotted proteins to adopt active conformations. A cell-free translation system in conjunction with pulse proteolysis to track folding of trefoil knotted proteins reveal that these knots form spontaneously, but GroEL–GroES enhances the rate of post-translational knot formation.
Polyketide synthases make use of a limited set of enzymes to create diverse natural products. The discovery that a ketosynthase homolog catalyzes ester bond formation instead of the typical Claisen condensation uncovers a previously unknown mechanism to generate chemical diversity.
A sensitive probe that detects protein sulfenylation in cells reveals that sulfenylation of the active site cysteine in EGFR enhances its kinase activity.
Biochemical and bioinformatic analyses have pointed to crotonyl-CoA carboxylase-reductase homolog as responsible for introducing unusual extender units into polyketide pathways; structural and mutational analysis now defines the basis for this reaction and the mechanism for substrate discrimination.
Enzymes that act on inositol pyrophosphates must accommodate a densely charged substrate while retaining excellent substrate specificity to control downstream signaling networks. Structural and biochemical data now define the basis for substrate recognition and the reaction coordinate for formation of a high-energy pyrophosphate bond.
DNA polymerases contain two cysteine-rich metal binding motifs (CysA and CysB), which have been assigned as zinc-ion binding sites by structural studies. A combination of biochemical and spectroscopic techniques reveal that the CysB site of yeast B-family polymerases binds a [4Fe-4S] cluster that is essential for polymerase function.
Lysophosphatidic acid (LPA), a lipid that induces neuropathic pain, functions by binding directly to the ion channel TRPV1 independently from the G protein–coupled receptors that generally mediate LPA function.
Single-molecule studies on a molecular motor F1-ATPase provide evidence that energy from catalysis is gradually converted to mechanical rotation, explaining the high efficiency of energy conversion and the mechanism for positive cooperativity among subunits during ATP hydrolysis.
An intramolecular cleft of the FAK FERM domain mediates interaction with sarcomeric myosin. Chemical cross-linking, SAXS and mutational analyses confirm the interaction, and inhibiting the interaction with a peptide activates FAK and promotes the cardiomyocyte hypertrophic response.
An orcein-related small molecule can drive polymerization of amyloid-β, implicated in Alzheimer's disease, without remodeling oligomeric or fibril forms but by stabilizing a seeding-competent protofilament state and shortening the lag phase of spontaneous polymerization.
The mass spectrometry and crystallographic characterization of an irreversible O-glycosyltransferase inhibitor surprisingly indicates that the dicarbamate core reacts to form an unusual carbonyl crosslink between two active site residues, probably driven by its ability to serve as a diphosphate mimic.
Genome-scale metabolic models provide a map of biochemical reactions in the cell but do not indicate how these reactions are regulated by complex transcriptional networks. Analysis of expression and interaction data now define two distinct roles for amino acids as signaling and nutrient molecules.
NMR and ITC are used to define essential features of a p38α phosphatase interface that extend beyond the classic KIM binding site, and SAXS analysis software, incorporating NMR chemical shift data, are developed and applied to build a model of the p38α-HePTP complex.
Coiled-coil assemblies have served as a rich resource for testing fundamental principles of protein structure and function. A semi-empirical design strategy now yields the first parallel hexamer, which also displays an internal channel that can be manipulated to direct assembly.
Conformation-specific antibodies and longitudinal tracking of individual neurons in situ identifies a toxic monomer species linked to Huntington's disease.
IMPDH and GMPR have similar active sites, but their reactions cause opposite effects on the guanine nucleotide pool. Biochemical and crystallographic evidence point to cofactor conformation as distinguishing the two reaction mechanisms and demonstrate that GMPR can substitute for IMPDH, prompting further investigations of this metabolic cycle.
