William S. Bennett

Structural and Functional Aspects of Domain Motions in Proteins

Three distinct categories of large-scale flexibility in proteins have been documented by single-crystal X-ray diffraction studies: the relatively free movement of essentially rigid globular domains that are connected by a flexible segment of polypeptide, the reorientation of essentially rigid domains among a few distinct conformations, and the concerted transition of a contiguous region of the surface of a protein from a disordered state to an ordered state. In a number of examples, well-defined functions can be assigned to these large-scale structural changes. The occurrence of such motions in proteins of known structure is reviewed, and the best-studied examples are discussed in detail to allow a critical evaluation of the methods used to identify and study these motions.

Crystallographic Studies on the Ribosome, a Large Macromolecular Assembly Exhibiting Severe Nonisomorphism, Extreme Beam Sensitivity and No Internal Symmetry

Crystals, diffracting best to around 3 A, have been grown from intact large and small ribosomal subunits. The bright synchrotron radiation necessary for the collection of the higher-resolution X-ray diffraction data introduces significant decay even at cryo temperatures. Nevertheless, owing to the reasonable isomorphism of the recently improved crystals of the small ribosomal subunits, reliable phases have been extracted at medium resolution (5-6 A) and an interpretable five-derivative MIR map has been constructed. For the crystals of the large subunits, however, the situation is more complicated because at higher resolution (2.7-7 A) they suffer from substantial radiation sensitivity, a low level of isomorphism, instability of the longest unit-cell axis and nonisotropic mosaicity. The 8 A MIR map, constructed to gain insight into this unusual system, may provide feasible reasoning for the odd combination of the properties of these crystals as well as hints for future improvement. Parallel efforts, in which electron-microscopy-reconstructed images are being exploited for molecular-replacement studies, are also discussed.

Dietary treatments of obesity.

Dietary treatment of obesity is based on one or another of two premises: that the obese eat too much or that they eat the wrong things. The first is a tautology lacking explanatory power. The second is a meaningful and promising hypothesis but has yet to be effectively applied. At present, virtually all outpatient treatments of obesity, including behavior modification, are based on the first premise and consist of strategies for reducing the subjects caloric intake. Most such interventions produce short-term weight loss. Regain after the end of treatment remains the usual outcome. A survey of studies published in the period 1977-1986 and reporting on dietary or behavioral treatment of obesity reveals that the maximum percentage of body weight lost is, on average, 8.5 percent--no different from the value, 8.9%, in similar studies from 1966-1976, as reviewed by Wing and Jeffery. The principal determinant of success in such programs appears to be the intake weight of the subjects: the higher the intake weight, the more successful the intervention will appear to be. The goals and research methods of studies on dietary treatments for obesity are overdue for ethical as well as scientific reevaluation. The same may be said for the numerous programs providing such treatment outside the context of research.

Aspects in Structural Studies on Ribosomes

(1992). Aspects in Structural Studies on Ribosomes. Critical Reviews in Biochemistry and Molecular Biology: Vol. 27, No. 4-5, pp. 403-444.

Towards Atomic Resolution of Prokaryotic Ribosomes: Crystallographic, Genetic and Biochemical Studies

The studies reported here were initiated and inspired by the late Prof. H.G. Wittmann. From the early stages of this project, when it was widely believed that even the initial steps in determining the molecular structure of ribosomes are impossible, until his last days, Prof. Wittmann was actively involved in the experimental design and in the actual studies. We have no doubt that without his motivation, optimism, guidance and support, this project would not have reached its current stage.

Ribosomal crystallography : from crystal growth to initial phasing

Preliminary phases were determined by the application of the isomorphous replacement method at low and intermediate resolution for structure factor amplitudes collected from crystals of large and small ribosomal subunits from halophilic and thermophilic bacteria. Derivatization was performed with dense heavy atom clusters, either by soaking or by specific covalent binding prior to the crystallization. The resulting initial electron density maps contain features comparable in size to those expected for the corresponding particles. The packing arrangements of these maps have been compared with motifs observed by electron microscopy in positively stained thin sections of embedded three-dimensional as well as with phase sets obtained by ab-initio computations. Aimed at higher resolution phasing, procedures are being developed for multi-site binding of relatively small dense metal clusters at selected locations. Potential sites are being inserted either by mutagenesis or by chemical modifications to facilitate cluster binding to the large halophilic and the small thermophil!c ribosomal subunits which yield crystals diffracting to the highest resolution obtained so far for ribosomes, 2.9 and 7.3 A, respectively. For this purpose the surfaces of these ribosomal particles have been characterized and conditions for quantitative reversible detachment of selected ribosomal proteins have been found. The corresponding genes are being cloned, sequenced, mutated to introduce the reactive side-groups (mainly cysteines) and overexpressed. To assist the interpretation of the anticipated electron density maps, sub-ribosomal stable complexes were isolated from H50S. One of these complexes is composed of two proteins and the other is made of a stretch of the rRNA and a protein. For exploiting the exposed parts of the surface of these complexes for heavy atom binding and for attempting the determination of their three-dimensional structure, their components are being produced genetically. The low resolution models reconstructed from tilt series of crystalline arrays of ribosomal particles are being employed for initial phasing. The tentative functional interpretation of these models stimulated the design and the crystallization of complexes mimicking

The identification of selected components in electron density maps of prokaryotic ribosomes at 7 Å resolution

Crystals of small and large ribosomal subunits from thermophilic and halophilic bacteria, diffracting to 3 A, are being subjected to structural analysis with synchrotron radiation. The bright beam necessary for detecting and collecting the diffraction at the higher-resolution shell causes significant decay even at 25 K. Nevertheless, data collected from native and heavy-atom-derivatized crystals led to the construction of electron density maps of both ribosomal subunits, showing recognizable morphologies and internal features similar to those observed by EM reconstructions of the corresponding ribosomal particle. The main features of these maps include elongated dense regions traceable as well separated RNA duplexes or single strands. Also seen are globular patches of lower density, readily distinguishable from the above, in which folds observed by NMR or crystallography in isolated ribosomal proteins at atomic resolution were detected. The intercomponents contacts identified so far reveal diverse modes of recognition. Metal clusters, attached at selected sites on the particles, are being exploited to facilitate unbiased map interpretation. In this way, two surface proteins were located and several surface RNA strands were targeted.

Enzymes as Biological Catalysts

Proteins perform many different functions in the living organism: enzymes are catalysts hormones are messengers in regulatory processes, immune proteins recognize, bind and, after a multi-step process, eliminate foreign molecules and cells regulatory proteins bind and modify the function of other macromolecules contractile proteins perform mechanical work, transport proteins move specific molecules across boundaries, e.g., through membranes, structural proteins form tissue, shells, etc.

Statistical Issues in Assessing the Aids Epidemic

Understanding the spread of AIDS and the virus that causes it is much more difficult than is generally recognized. The hope of predicting even the size of the epidemic over the next fifteen years, let alone the population groups that will be affected, is limited by lack of information about the natural history of AIDS and the infectivity of HIV, and by our sketchy knowledge of sexual and needle-sharing behavior.

Coffin nails and corporate strategies: by Robert H. Miles in collaboration with Kim S. Cameron. Prentice-Hall, Englewood Cliffs, NJ. 298 pp.

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