Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
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In this article we focus on presenting a broad range of examples illustrating low-energy transitions via hinge-bending motions. The examples are divided according to the type of hinge-bending involved; namely, motions involving fragments of the protein chains, hinge-bending motions involving protein domains, and hinge-bending motions between the covalently unconnected subunits. We further make a distinction between allosterically and nonallosterically regulated proteins. These transitions are discussed within the general framework of folding and binding funnels. We propose that the conformers manifesting such swiveling motions are not the outcome of "induced fit" binding mechanism; instead, molecules exist in an ensemble of conformations that are in equilibrium in solution. These ensembles, which populate the bottoms of the funnels, a priori contain both the "open" and the "closed" conformational isomers. Furthermore, we argue that there are no fundamental differences among the physical principles behind the folding and binding funnels. Hence, there is no basic difference between funnels depicting ensembles of conformers of single molecules with fragment, or domain motions, as compared to subunits in multimeric quaternary structures, also showing such conformational transitions. The difference relates only to the size and complexity of the system. The larger the system, the more complex its corresponding fused funnel(s). In particular, funnels associated with allosterically regulated proteins are expected to be more complicated, because allostery is frequently involved with movements between subunits, and consequently is often observed in multichain and multimolecular complexes. This review centers on the critical role played by flexibility and conformational fluctuations in enzyme activity. Internal motions that extend over different time scales and with different amplitudes are known to be essential for the catalytic cycle. The conformational change observed in enzyme-substrate complexes as compared to the unbound enzyme state, and in particular the hinge-bending motions observed in enzymes with two domains, have a substantial effect on the enzymatic catalytic activity. The examples we review span the lipolytic enzymes that are particularly interesting, owing to their activation at the water-oil interface; an allosterically controlled dehydrogenase (lactate dehydrogenase); a DNA methyltransferase, with a covalently-bound intermediate; large-scale flexible loop motions in a glycolytic enzyme (TIM); domain motion in PGK, an enzyme which is essential in most cells, both for ATP generation in aerobes and for fermentation in anaerobes; adenylate kinase, showing large conformational changes, owing to their need to shield their catalytic centers from water; a calcium-binding protein (calmodulin), involved in a wide range of cellular calcium-dependent signaling; diphtheria toxin, whose large domain motion has been shown to yield "domain swapping;" the hexameric glutamate dehydrogenase, which has been studied both in a thermophile and in a mesophile; an allosteric enzyme, showing subunit motion between the R and the T states (aspartate transcarbamoylase), and the historically well-studied lac repressor. Nonallosteric subunit transitions are also addressed, with some examples (aspartate receptor and BamHI endonuclease). Hence, using this enzyme-catalysis-centered discussion, we address energy funnel landscapes of large-scale conformational transitions, rather than the faster, quasi-harmonic, thermal fluctuations.
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PMID:Folding funnels and conformational transitions via hinge-bending motions. 1059 56

To gain further insight into the basis for the extended longevity and delayed aging of Snell dwarf (dw/dw) mice, we have measured levels of expression of 2352 genes in liver of mice at 6 months of age. We find 60 genes for the which the Student's t statistic meets the arbitrary criterion of p <.001, and among these 17 meet the Bonferroni-adjusted significance criterion at p <.05, which corresponds to a nominal value of p <.00002. Using the Bonferroni criterion, we find that dwarf mice show increases in liver mRNA for two mannose-binding lectins, two DNA binding proteins, serum amyloid P component, corticosteroid-binding globulin, and insulin-like growth factor-binding protein 2, as well as decreases in a two phosphodiesterases, a pheromone-binding urinary protein, insulin-like growth factor-I (IGF-I), a calcium-binding protein calgranulin B, a deubiquitinating enzyme, a hydroxysteroid dehydrogenase, a DNA methyltransferase, a glycine transporter, and a placental lactogen. We also use this data set to compare the results of different suggested criteria for evaluating intergroup differences in gene expression. Of the 2352 genes examined, 524 (22%) showed a twofold difference between dwarf and normal mice, but most of these fail to meet the conventional significance criterion of p <.05, let alone criteria that have been adjusted to compensate for multiple comparison artifacts. The list of genes that show reliable differences between dwarf and control animals provides new insights into the range of changes induced by deficiencies in growth hormone, thyroid-stimulating hormone, and prolactin, and it will help to guide further studies of the pathways by which these hormone deficiencies contribute to delayed aging in these mutant mice.
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PMID:Gene expression profile of long-lived snell dwarf mice. 1186 46