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Near-atomistic models of the prepore and membrane-inserted pore conformations derived from a combination of crystallography, cryo-EM, single-particle analysis, molecular simulation and modeling reveal a swirling mechanism of membrane insertion and pore formation by aerolysin.
Two families of sulfotransferases are known, but the natural sulfate source for the PAPS-independent enzymes was not clear. Investigation of the caprazamycin pathway reveals a type III PKS generates a chemical reagent that is sulfated by a PAPS-dependent sulfotransferase to generate the unknown sulfate donor.
A small-molecule activator of Wnt/β-catenin signaling acts by binding a negative regulator of β-catenin, Axin, leading to a conformational change that promotes association of Axin with LRP6.
The VCP ATPase has been linked to cancer, but the lack of well-defined, selective inhibitors has limited further investigation. A million-molecule screen now identifies a covalent inhibitor as well as an allosteric inhibitor that may freeze the enzyme in an ADP-bound conformation.
Monitoring the half-life of mutant huntingtin protein reveals how specific neurons are more susceptible to its toxic effects and to Huntington's disease.
Heterotrimeric G proteins contain a switch III motif that regulates enzyme function. Structural and biochemical studies now identify a similar switch III loop in a nonheterotrimeric G-protein chaperone that explains the debilitating effects of mutations linked to methylmalonic aciduria.
Structural and thermodynamic characterization of the interaction between the intrinsically disordered HBV protein preS1 and the human adaptor protein γ2-EAR indicates that the viral protein imitates host cell interaction motifs to gain access to the cellular trafficking system.
LuxR receptor and LuxI synthase homologs coordinate quorum sensing in several bacterial species. Investigations of a LuxR family member that is missing a LuxI partner define a pheromone signaling circuit that coordinates cell clumping based on recognition of its newly discovered ligands, the photopyrones.
An inhibitor of oxysterol-induced Smoothened activation defines a 20-OHC binding site in the extracellular domain of this essential component of the Hedgehog signaling pathway.
Mapping the yeast ABC transporter interactome suggests functional significance of transporter-transporter interactions and also shows function of some transporters in zinc homeostasis.
Thiophene compounds kill M. tuberculosis by inhibiting Pks13, demonstrating that the enzyme catalyzes a critical step in biosynthesis of mycolic acids in vivo.
A previously designed enzyme used a reactive lysine to initiate cleavage of a carbon-carbon bond. Directed evolution of this construct now shows a drastic reorganization of the active site to use an alternative catalytic lysine and suggests considerations for future design efforts.
A Kv1 channel inhibitor and potential therapeutic lead achieves selectivity by binding both the conserved central cavity and newly identified side pockets, which provide the key determinants for channel specificity.
A high-throughput chemical screen of primary human hepatocytes in combination with machine-learning algorithms for evaluation of imaging data identifies compounds that promote expansion of primary human hepatocytes and maturation from human iPS cells toward an adult-like hepatocyte phenotype.
Studies of histidine phosphorylation have been limited owing to a lack of appropriate tools. The synthesis of a stable phosphohistidine mimic now leads to a pan antibody, enabling detection and further functional investigations of this little-known post-translational modification.
ATP-competitive RAF kinase inhibitors stabilize a closed and rigid active conformation of the RAF kinase domain, which leads to RAF dimerization and allosteric activation of the inhibitor-free protomer.
Certain oxidative DNA lesions adopt altered conformational preferences that lead to mutations during replication. Biochemical and structural data reveal that for formamidopyrimidine lesions, tautomerization and altered base pair geometry in the DNA polymerase active site, rather than changes in glycosidic torsion angle, direct the mutagenicity of these lesions.