The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding.

[1] We present evidence based on measurements from the Polar spacecraft for the existence of small-scale, large-amplitude kinetic Alfvén waves/spikes at the plasma sheet boundary layer (PSBL) at altitudes of 4-6 R E . These structures coincide with larger-scale Alfvénic waves that carry a large net Poynting flux along magnetic field lines toward the Earth. Both structures are typically observed in the PSBL but have also been observed deeper in the plasma sheet. The small-scale spikes have electric field amplitudes up to 300 mV m À1 and associated magnetic field variations between 0.5 and 5 nT. Previous analysis has shown that the larger-scale Alfvén waves have periods of $20-60 s and carry enough Poynting flux to explain the generation of the most intense auroral structures observed in the Polar Ultraviolet Imager data set. In this paper it is shown that the smaller-scale waves have durations in the spacecraft frame of 250 ms to 1 s (but may have shorter time durations since the Nyquist frequency of the magnetic field experiment is $4 Hz.). The characteristic ratio of the amplitudes of the electric to magnetic field fluctuations is strong evidence that the waves are kinetic Alfvén waves with scale sizes perpendicular to the magnetic field on the order of 20-120 km (with an electron inertial length c/w pe $10 km and an ion gyroradius $20 km). Theoretical analysis of the observed spikes suggests that these waves should be very efficient at accelerating electrons parallel to the magnetic field. Simultaneously measured electron velocity space distribution functions from the Polar Hydra instrument include parallel electron heating features and earthward electron beams, indicating strong parallel energization. The characteristic parallel energy is on the order of $1 keV, consistent with estimates of the parallel R Edl associated with small-scale kinetic Alfvén wave structures. The energy flux in the electron ''beams'' is $0.7 ergs cm À2 s À1 . These observations suggest that the small-scale kinetic Alfvén waves are generated from the larger-scale Alfvén waves through one or more of a variety of mechanisms that have been proposed to result in the filamentation of large-amplitude Alfvén waves. The observations presented herein provide strong evidence that in addition to the auroral particle energization processes known to occur at altitudes between 0.5 and 2 R E , there are important heating and acceleration mechanisms operating at these higher altitudes in the plasma sheet.

No abstract

Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.