Publications

Conformation space of a heterodimeric ABC exporter under turnover conditions.

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Our findings reveal that phosphate release, not ATP hydrolysis, triggers the return of the exporter to the IF conformation. By mapping the conformational landscape during active turnover, aided by mutational and chemical modulation of kinetic rates to trap the key intermediates, we resolved fundamental steps of the substrate translocation cycle of asymmetric ABC transporters.

Conformation space of a heterodimeric ABC exporter under turnover conditions. Read More »

Know your detergents: A case study on detergent background in negative stain electron microscopy

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Electron cryo-microscopy (cryo-EM) of purified macromolecular complexes is now providing 3D-structures at near-atomic resolution (Kühlbrandt, 2014). Cryo-EM can tolerate heterogeneous specimens, however, high-resolution efforts demand highly optimized samples.

Know your detergents: A case study on detergent background in negative stain electron microscopy Read More »

The Immunomodulatory Drug Glatiramer Acetate is Also an Effective Antimicrobial Agent that Kills Gram-negative Bacteria

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Classic drug development strategies have failed to meet the urgent clinical needs in treating infections with Gram-negative bacteria. Repurposing drugs can lead to timely availability of new antibiotics, accelerated by existing safety profiles. Glatiramer acetate (GA) is a widely used and safe formulation for treatment of multiple sclerosis.

The Immunomodulatory Drug Glatiramer Acetate is Also an Effective Antimicrobial Agent that Kills Gram-negative Bacteria Read More »

Structure of the human MHC-I peptide-loading complex

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The peptide-loading complex (PLC) is a transient, multisubunit membrane complex in the endoplasmic reticulum that is essential for establishing a hierarchical immune response. The PLC coordinates peptide translocation into the endoplasmic reticulum with loading and editing of major histocompatibility complex class I (MHC-I) molecules.

Structure of the human MHC-I peptide-loading complex Read More »

Cryo-EM structure of the replisome reveals multiple interactions coordinating DNA synthesis

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The antiparallel nature of the two strands in duplex DNA poses a topological problem for their simultaneous synthesis. The “trombone” model of the replication fork postulates that the lagging-strand forms a loop such that the leading- and lagging-strand replication proteins contact one another.

Cryo-EM structure of the replisome reveals multiple interactions coordinating DNA synthesis Read More »

Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Article Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin

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Sortilin is a neuronal receptor involved in transmembrane signaling, endocytosis, and intracellular sorting of proteins. It cycles through a number of cellular compartments where it encounters various acidic conditions. The crystal structure of the sortilin ectodomain has previously been determined at neutral pH. Here, we present the 3.5-Å resolution crystal structure of sortilin at pH 5.5, which represents an environment similar to that of late endosomes, where ligands are released.

Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Article Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin Read More »

Pellet-free isolation of human and bovine milk extracellular vesicles by size-exclusion chromatography.

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Studies have suggested that nanoscale extracellular vesicles (EV) in human and bovine milk carry immune modulatory properties which could provide beneficial health effects to infants. In order to assess the possible health effects of milk EV, it is essential to use isolates of high purity from other more abundant milk structures with well-documented bioactive properties.

Pellet-free isolation of human and bovine milk extracellular vesicles by size-exclusion chromatography. Read More »

Hidden Twins: SorCS neuroreceptors form stable dimers. J Mol Biol

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SorCS1, SorCS2 and SorCS3 belong to the Vps10p-domain family of multiligand receptors. Genetic and functional studies have linked SorCS receptors to psychiatric disorders, Alzheimer’s disease and type 2 diabetes, demonstrating critical roles in neuronal functionality and metabolic control.

Hidden Twins: SorCS neuroreceptors form stable dimers. J Mol Biol Read More »

Division of labor in transhydrogenase by alternating proton translocation and hydride transfer.

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NADPH/NADP+ (the reduced form of NADP+/nicotinamide adenine dinucleotide phosphate) homeostasis is critical for countering oxidative stress in cells. Nicotinamide nucleotide transhydrogenase (TH), a membrane enzyme present in both bacteria and mitochondria, couples the proton motive force to the generation of NADPH. We present the 2.8 Å crystal structure of the transmembrane proton channel domain of TH from Thermus thermophilus and the 6.9 Å crystal structure of the entire enzyme (holo-TH).

Division of labor in transhydrogenase by alternating proton translocation and hydride transfer. Read More »

Distinct conformational spectrum of homologous multidrug ABC transporters.

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ATP-binding cassette (ABC) exporters are ubiquitously found in all kingdoms of life and their members play significant roles in mediating drug pharmacokinetics and multidrug resistance in the clinic. Here, we used single particle electron microscopy (EM) to delineate the entire conformational spectrum of two homologous ABC exporters (bacterial MsbA and mammalian P-glycoprotein) and the influence of nucleotide and substrate binding.

Distinct conformational spectrum of homologous multidrug ABC transporters. Read More »