Carboxylate shifts are often important for carboxylate coordinated metal clusters; they allow the metals to achieve different coordination modes in redox reactions. In the case of reduced R2 these carboxylate shifts allow the formation of accessible reaction sites for dioxygen. The Ser211--> Ala mutant displays a conformational change in the helix containing the mutation, explaining its altered reduction kinetics.

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Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low levels, and a defensive cytotoxin at higher levels. The high active-site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock, and cancer. Our structural and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a novel specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents towards remote specificity pockets, accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active-site conservation.

The crystal structure at 2.7 A resolution of histidyl-tRNA synthetase (HisRS) from Thermus thermophilus in complex with its amino acid substrate histidine has been determined. In the crystal asymmetric unit there are two homodimers, each subunit containing 421 amino acid residues. Each monomer of the enzyme consists of three domains: (1) an N-terminal catalytic domain containing a six-stranded antiparallel beta-sheet and the three motifs common to all class II aminoacyl-tRNA synthetases, (2) a 90-residue C-terminal alpha/beta domain which is common to most class IIa synthetases and is probably involved in recognizing the anticodon stem-loop of tRNA(His), and (3) a HisRS-specific alpha-helical domain inserted into the catalytic domain, between motifs II and III. The position of the insertion domain above the catalytic site suggests that it could clamp onto the acceptor stem of the tRNA during aminoacylation. Two HisRS-specific peptides, 259-RGLDYY and 285-GGRYDG, are intimately involved in forming the binding site for the histidine, a molecule of which is found in the active site of each monomer. The structure of HisRS in complex with histidyl adenylate, produced enzymatically in the crystal, has been determined at 3.2 A resolution. This structure shows that the HisRS-specific Arg-259 interacts directly with the alpha-phosphate of the adenylate on the opposite side to the usual conserved motif 2 arginine. Arg-259 thus substitutes for the divalent cation observed in seryl-tRNA synthetase and plays a crucial catalytic role in the mechanism of histidine activation.

Acupuncture relieves low-back and pelvic pain without serious adverse effects in late pregnancy.

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SUMMARY Ten annual cohorts of men suffering from their first myocardial infarction have been followed up to a maximum period of 10.5 years. One thousand and twenty-three male patients of 1306 were smokers. Three months after the infarction 55% had stopped smoking and 45% continued smoking. These two groups were then compared and followed with regard to non-fatal reinfarctions and deaths.Preinfarction characteristics were shown to be similar for the two groups. The prognostic comparability of the two groups was tested using two multiple logistic models. Those who stopped smoking had a slightly higher predicted two year mortality after the infarction. In different age groups it is shown with life table technique that those who stopped smoking had a considerably higher survival rate and lower cumulative frequency of reinfarction.The present study shows a reversion of the expected prognosis after myocardial infarction caused by changing the smoking habit.Cigarette smoking is one of the major risk factors for the development of coronary heart disease.' I-In a previous report we have shown the beneficial effects of stopping smoking after myocardial infarction. Those who stopped smoking had only half the cardiovascular mortality rate and only half the rate of non-fatal recurrences compared with those who continued to smoke.4 An increased death rate among those who continue to smoke has also been shown by others. S-7 The aim of the present study was to investigate whether our early findings were stable or even enhanced during a prolonged follow-up, and if the proposed effect of changing the smoking habit differed in certain age-groups. Patients and methodsAs from 1 January 1968, all cases of myocardial infarction occurring in Goteborg have been registered by the MI Register.8 The present study comprised men who suffered their first myocardial infarction and