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.

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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.

The electron density distribution and 3d-orbital electron occupancies for the Fe atom in synthetic triphylite, LiFePO4, have been analysed using single-crystal X-ray diffraction data measured at T= 298 K with Mo Ka (3. =0.71069 ,~) radiation to a resolution corresponding to (sinOmax/3.)= 1.078 ,~-~. Measurements of 3265 reflections gave 944 unique data [Rint(I) = 0.036] with I > 2o,(1). For an atomic multipole density model fitted by least-squares methods R(F) = 0.0174 for all unique reflections. The Fe atom 3d-orbital occupancies have been derived from the multipole population coefficients using point-groupspecific relations. The asphericity of the electron deformation density around the Fe atom is discussed using crystal-field theory and magnetic properties of triphylite. Crystal data: lithium iron(II) phosphate, IntroductionThe crystal structure of LiFePO4, which has been studied by Yakubovich, Simonov & Belov (1977) and described in more detail by Yakubovich, Belokoneva, Tsirelson & Urusov (1990), has an olivine-type structure with a distorted hexagonal * Author to whom correspondence should be addressed. Present address: Crystallography Centre, University of Western Australia, Nedlands, Western Australia 6009, Australia.0108-7681/93/020147-07506.00 anion close packing, where the cations occupy three different positions: a tetrahedral (P) site and two octahedral sites. An ORTEP (Johnson, 1965) plot showing the cation coordination is given in Fig. 1. One octahedral site lies at the inversion centre and the other is in the mirror plane. As usual in olivinetype structures the former octahedral site is occupied by cations with smaller charge (Li) and the latter by cations with larger charge (Fe). The main feature of the LiFePO4 crystal structure consists of olivine-type ribbons extending along the b crystal axis. The Li octahedra protrude from the olivine ribbon and are connected along their edges and with the larger Fe © 1993 International Union of Crystallography 148 LiFePO4 octahedra. PO4 tetrahedra have three of the six edges in common with the cation octahedra. These edges have the shortest lengths and differ significantly from the other O---O distances.The magnetic structure of LiFePO4 has been determined by Santoro & Newnham (1967) from neutron diffraction data. Below the N~el temperature TN = 50 K, the spin vectors associated with these Fe-atom positions are antiparallel and align in an antiferromagnetic array collinear with the b axis. The magnetic space group is Pnma'. AS has been shown (Santoro & Newnham, 1967), the only Fe O---Fe superexchange interactions give rise to antiferromagnetic puckered planes orthogonal to a. There are no direct or superexchange linkages between these planes, and long-range interactions, such as Fe---O---P--O--Fe triple exchange, have been suggested.The present paper describes a study of the electron deformation density in synthetic crystalline triphylite, LiFePO4. A multipole refinement of the X-ray diffraction data has been carried out using different approxim...

Neurodegeneration observed in Alzheimer disease (AD) is believed to be related to the toxicity from reactive oxygen species (ROS) produced in the brain by the amyloid-beta (Abeta) protein bound primarily to copper ions. The evidence for an oxidative stress role of Abeta-Cu redox chemistry is still incomplete. Details of the copper binding site in Abeta may be critical to the etiology of AD. Here we present the structure determined by combining x-ray absorption spectroscopy (XAS) and density functional theory analysis of Abeta peptides complexed with Cu(2+) in solution under a range of buffer conditions. Phosphate-buffered saline buffer salt (NaCl) concentration does not affect the high-affinity copper binding mode but alters the second coordination sphere. The XAS spectra for truncated and full-length Abeta-Cu(2+) peptides are similar. The novel distorted six-coordinated (3N3O) geometry around copper in the Abeta-Cu(2+) complexes include three histidines: glutamic, or/and aspartic acid, and axial water. The structure of the high-affinity Cu(2+) binding site is consistent with the hypothesis that the redox activity of the metal ion bound to Abeta can lead to the formation of dityrosine-linked dimers found in AD.

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