Key Points
HLA-DRB1*07:01 is associated with asparaginase hypersensitivity and anti-asparaginase antibodies. HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of hypersensitivity.
Cooper pairs in non-centrosymmetric superconductors can acquire finite centre-of-mass momentum in the presence of an external magnetic field. Recent theory predicts that such finite-momentum pairing can lead to an asymmetric critical current, where a dissipationless supercurrent can flow along one direction but not in the opposite one. Here we report the discovery of a giant Josephson diode effect in Josephson junctions formed from a type-II Dirac semimetal, NiTe2. A distinguishing feature is that the asymmetry in the critical current depends sensitively on the magnitude and direction of an applied magnetic field and achieves its maximum value when the magnetic field is perpendicular to the current and is of the order of just 10 mT. Moreover, the asymmetry changes sign several times with an increasing field. These characteristic features are accounted for by a model based on finite-momentum Cooper pairing that largely originates from the Zeeman shift of spin-helical topological surface states. The finite pairing momentum is further established, and its value determined, from the evolution of the interference pattern under an in-plane magnetic field. The observed giant magnitude of the asymmetry in critical current and the clear exposition of its underlying mechanism paves the way to build novel superconducting computing devices using the Josephson diode effect.
The declining effectiveness of current
antibiotics due to the emergence
of resistant bacterial strains dictates a pressing need for novel
classes of antimicrobial therapies, preferably against molecular sites
other than those in which resistance mutations have developed. Dihydropteroate
synthase (DHPS) catalyzes a crucial step in the bacterial pathway
of folic acid synthesis, a pathway that is absent in higher vertebrates.
As the target of the sulfonamide class of drugs that were highly effective
until resistance mutations arose, DHPS is known to be a valuable bacterial
Achilles heel that is being further exploited for antibiotic development.
Here, we report the discovery of the first known allosteric inhibitor
of DHPS. NMR and crystallographic studies reveal that it engages a
previously unknown binding site at the dimer interface. Kinetic data
show that this inhibitor does not prevent substrate binding but rather
exerts its effect at a later step in the catalytic cycle. Molecular
dynamics simulations and quasi-harmonic analyses suggest that the
effect of inhibitor binding is transmitted from the dimer interface
to the active-site loops that are known to assume an obligatory ordered
substructure during catalysis. Together with the kinetics results,
these structural and dynamics data suggest an inhibitory mechanism
in which binding at the dimer interface impacts loop movements that
are required for product release. Our results potentially provide
a novel target site for the development of new antibiotics.
Salt influences protein stability through electrostatic mechanisms as well as through nonpolar Hofmeister effects. In the present work, a continuum solvation based model is developed to explore the impact of salt on protein stability. This model relies on a traditional Poisson-Boltzmann (PB) term to describe the polar or electrostatic effects of salt, and a surface area dependent term containing a salt concentration dependent microscopic surface tension function to capture the non-polar Hofmeister effects. The model is first validated against a series of cold-shock protein variants whose salt-dependent protein fold stability profiles have been previously determined experimentally. The approach is then applied to HIV-1 protease in order to explain an experimentally observed enhancement in stability and activity at high (1M) NaCl concentration. The inclusion of the salt-dependent non-polar term brings the model into quantitative agreement with experiment, and provides the basis for further studies into the impact of ionic strength on protein structure, function, and evolution.
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