Bottom-up design of calcium channels from defined selectivity filter geometry.

Native ion channels play key roles in biological systems, and engineered versions are widely used as chemogenetic tools and in sensing devices . Protein design has been harnessed to generate pore-containing transmembrane proteins, but the capability to design ion selectivity based on the interactions between ions and selectivity filter residues, a crucial feature of native ion channels , has been constrained by the lack of methods to place the metal-coordinating residues with atomic-level precision. Here we describe a bottom-up RFdiffusion-based approach to construct Ca channels from defined selectivity filter residue geometries, and use this approach to design symmetric oligomeric channels with Ca selectivity filters having different coordination numbers and different geometries at the entrance of a wide pore buttressed by multiple transmembrane helices.

Four-component protein nanocages designed by programmed symmetry breaking.

Four, eight or twenty C3 symmetric protein trimers can be arranged with tetrahedral, octahedral or icosahedral point group symmetry to generate closed cage-like structures. Viruses access more complex higher triangulation number icosahedral architectures by breaking perfect point group symmetry, but nature appears not to have explored similar symmetry breaking for tetrahedral or octahedral symmetries. Here we describe a general design strategy for building higher triangulation number architectures starting from regular polyhedra through pseudosymmetrization of trimeric building blocks.

Structural Convergence and Water-Mediated Substrate Mimicry Enable Broad Neuraminidase Inhibition by Human Antibodies.

Influenza has been responsible for multiple global pandemics and seasonal epidemics and claimed millions of lives. The imminent threat of a panzootic outbreak of avian influenza H5N1 virus underscores the urgent need for pandemic preparedness and effective countermeasures, including monoclonal antibodies (mAbs). Here, we characterize human mAbs that target the highly conserved catalytic site of viral neuraminidase (NA), termed NCS mAbs, and the molecular basis of their broad specificity.

Targeted medical therapies for vascular anomalies.

The last 2 decades of genetic discovery in the field of vascular anomalies have brought targeted medical therapies to the forefront of care patients with vascular anomalies and have broadened the role of hematologists/oncologists in this field. Many vascular anomalies have now been identified to be driven by somatic gain-of-function variants in the PI3K/AKT/ mTOR and Ras/MAPK intracellular signaling pathways. This has led to the introduction of various antiangiogenic agents that inhibit these pathways.

Biased cell adhesion organizes the Drosophila visual motion integration circuit.

Layer-specific brain computations depend on neurons synapsing with specific partners in distinct laminae. In the Drosophila lobula plate, axons of the four subtypes of T4 and T5 visual motion direction-selective neurons segregate into four layers, where they synapse with distinct subsets of postsynaptic neurons. Here, we identify a layer-specific expression of different receptor-ligand pairs of the Beat and Side families of cell adhesion molecules between T4/T5s and their postsynaptic partners.