Huber RG
Allosteric Kinase Inhibitors Reshape MEK1 Kinase Activity Conformations in Cells and In Silico
Mutations at different stages of the mitogen-activated protein kinase (MAPK) signaling pathway lead to aberrant activation of the involved protein kinase entities. These oncogenic modifications alter signal propagation which converge on the gatekeeper kinases MEK1/2, transmitting the input signal to ERK1/2.
ReadThe Pseudo-Circular Genomes of Flaviviruses: Structures, Mechanisms, and Functions of Circularization
The circularization of viral genomes fulfills various functions, from evading host defense mechanisms to promoting specific replication and translation patterns supporting viral proliferation. Here, we describe the genomic structures and associated host factors important for flaviviruses genome circularization and summarize their functional roles.
ReadAntibody affinity versus dengue morphology influences neutralization
Different strains within a dengue serotype (DENV1-4) can have smooth, or “bumpy” surface morphologies with different antigenic characteristics at average body temperature (37°C). We determined the neutralizing properties of a serotype cross-reactive human monoclonal antibody (HMAb) 1C19 for strains with differing morphologies within the DENV1 and DENV2 serotypes.
ReadMutation-oriented profiling of autoinhibitory kinase conformations predicts RAF inhibitor efficacies
The pharmaceutical targeting of mutated BRAF has shown promising clinical outcomes in patients with melanoma. However, more than 300 reported BRAF patient mutations and the occurrence of a kinase-drug resistance mechanism hamper patient-oriented therapies. We have developed an extendable and cell-based kinase conformation reporter platform (KinCon) to predict and compare the effect of kinase drugs. We systematically evaluated drug efficacies by assessing KinCon reporter dynamics in response to different drugs and patient mutations. Our findings suggest that FDA-approved melanoma inhibitors may have the potential to block non-V600E–mutated BRAF activities also in non–small-cell lung cancers (NSCLC). We assume that widespread analyses of KinCon:drug interactions may assist in the future in identifying patient mutation–specific and thus more effective kinase inhibitors.
ReadMolecular simulations unravel the molecular principles that mediate selective permeability of carboxysome shell protein
Bacterial microcompartments (BMCs) are nanoscale proteinaceous organelles that encapsulate enzymes from the cytoplasm using an icosahedral protein shell that resembles viral capsids. Of particular interest are the carboxysomes (CBs), which sequester the CO2-fixing enzymes ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) to enhance carbon assimilation.
ReadThe Molecular Basis for Purine Binding Selectivity in the Bacterial ATP Synthase ϵ Subunit
The ϵ subunit of ATP synthases has been proposed to regulate ATP hydrolysis in bacteria. Prevailing evidence supports the notion that when the ATP concentration falls below a certain threshold, the ϵ subunit changes its conformation from a non‐inhibitory down‐state to an extended up‐state that then inhibits enzymatic ATP hydrolysis by binding to the catalytic domain.
Read3D reconstruction and flexibility of the hybrid engine Acetobacterium woodii F-ATP synthase
The Na+-translocating F1FO ATP synthase from Acetobacterium woodii (AwF-ATP synthase) with a subunit stoichiometry of α3:β3:γ:δ:ε:a:b2:(c2/3)9:c1 represents an evolutionary path between ATP-synthases and vacuolar ATPases, by containing a heteromeric rotor c-ring, composed of subunits c1, c2 and c3, and an extra loop (γ195-211) within the rotary γ subunit.
ReadComputational modelling of flavivirus dynamics: The ins and outs
- Computational methods integrating experimental data help elucidate viral life cycle. - Viruses are dynamic and have complex interactions with a variety of host factors. - We can now model the complex interplay of proteomic and genomic components. - Molecular biology, genomics, and computation complement structural methods.
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