Elucidating pathological fibril structure: Amyloid-β (Aβ) is a key pathological contributor to Alzheimer's disease. Gremer et al. used cryoelectron microscopy data to build a high-quality de novo atomic model of Aβ fibrils (see the Perspective by Pospich and Raunser). The complete structure reveals all 42 amino acids (including the entire N terminus) and provides a structural basis for understanding the effect of several disease-causing and disease-preventing mutations. The fibril consists of two intertwined protofilaments with an unexpected dimer interface that is different from those proposed previously. The structure has implications for the mechanism of fibril growth and will be an important stepping stone to rational drug design. Science , this issue p. 116 ; see also p. 45

The homodimeric nickel-containing CO dehydrogenase from the anaerobic bacterium Carboxydothermus hydrogenoformans catalyzes the oxidation of CO to CO ₂ . A crystal structure of the reduced enzyme has been solved at 1.6 angstrom resolution. This structure represents the prototype for Ni-containing CO dehydrogenases from anaerobic bacteria and archaea. It contains five metal clusters of which clusters B, B′, and a subunit-bridging, surface-exposed cluster D are cubane-type [4Fe-4S] clusters. The active-site clusters C and C′ are novel, asymmetric [Ni-4Fe-5S] clusters. Their integral Ni ion, which is the likely site of CO oxidation, is coordinated by four sulfur ligands with square planar geometry.

The CO dehydrogenase of the eubacterium Oligotropha carboxidovorans is a 277-kDa Mo- and Cu-containing iron-sulfur flavoprotein. Here, the enzyme's active site in the oxidized or reduced state, after inactivation with potassium cyanide or with n-butylisocyanide bound to the active site, has been reinvestigated by multiple wavelength anomalous dispersion measurements at atomic resolution, electron spin resonance spectroscopy, and chemical analyses. We present evidence for a dinuclear heterometal [CuSMo( O)OH] cluster in the active site of the oxidized or reduced enzyme, which is prone to cyanolysis. The cluster is coordinated through interactions of the Mo with the dithiolate pyran ring of molybdopterin cytosine dinucleotide and of the Cu with the Sγ of Cys-388, which is part of the active-site loop VAYRC ³⁸⁸ SFR. The previously reported active-site structure [Dobbek, H., Gremer, L., Meyer, O. & Huber, R. (1999) Proc. Natl. Acad. Sci. USA 96, 8884–8889] of an Mo with three oxygen ligands and an SeH-group bound to the Sγ atom of Cys-388 could not be confirmed. The structure of CO dehydrogenase with the inhibitor n-butylisocyanide bound has led to a model for the catalytic mechanism of CO oxidation which involves a thiocarbonate-like intermediate state. The dinuclear [CuSMo( O)OH] cluster of CO dehydrogenase establishes a previously uncharacterized class of dinuclear molybdoenzymes containing the pterin cofactor.

Martin Zenker, Marco Tartaglia, Reza Ahmadian and colleagues report the identification of a restricted spectrum of NRAS mutations in individuals with Noonan syndrome. Functional testing revealed that the mutations confer enhanced stimulus-dependent MAPK activation. Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway. Here we report that germline NRAS mutations conferring enhanced stimulus-dependent MAPK activation account for some cases of this disorder. These findings provide evidence for an obligate dependency on proper NRAS function in human development and growth.

CO dehydrogenase from the aerobic bacterium Oligotropha carboxidovorans catalyzes the oxidation of CO with H ₂ O, yielding CO ₂ , two electrons, and two H ⁺ . Its crystal structure in the air-oxidized form has been determined to 2.2 Å. The active site of the enzyme, which contains molybdenum with three oxygen ligands, molybdopterin-cytosine dinucleotide and S -selanylcysteine, delivers the electrons to an intramolecular electron transport chain composed of two types of [2Fe–2S] clusters and flavin-adenine dinucleotide. CO dehydrogenase is composed of an 88.7-kDa molybdoprotein (L), a 30.2-kDa flavoprotein (M), and a 17.8-kDa iron-sulfur protein (S). It is organized as a dimer of LMS heterotrimers and resembles xanthine dehydrogenase/oxidase in many, but not all, aspects. A mechanism based on a structure with the bound suicide-substrate cyanide is suggested and displays the necessity of S -selanylcysteine for the catalyzed reaction.