Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nucleotides in the bifurcation region of the 5 S rRNA, the junction of the three helical domains, play a central role in determining the coaxial stacking interactions and tertiary structure of the RNA. We have used site-directed mutagenesis of Xenopus laevis oocyte 5 S rRNA to make all possible nucleotide substitutions at three positions in loop A (10, 11 and 13) and at the G66.U109 base-pair at the beginning of helix V. Certain double point mutations were constructed to ascertain the relationship between loop A nucleotides and the G.U base-pair. The importance of the size of the bifurcation region was tested by the creation of a single nucleotide deletion mutant and two single nucleotide insertion mutants. The effects of these mutations on the structure and function of the 5 S rRNA were determined by solution structure probing of approximately half of the mutants with chemical reagents, and by measuring the relative binding affinity of each mutant for transcription factor TFIIIA. Proposed structural rearrangements in the bifurcation region were tested by using a graphic modeling method combining stereochemical constraints and chemical reactivity data. From this work, several insights were obtained into the general problem of helix stacking and RNA folding at complex bifurcation regions. None of the mutations caused an alteration of the coaxial stacking of helix V on helix II proposed for the wild-type 5 S rRNA. However, the formation of a Watson-Crick pair between nucleotide 13 of loop A and nucleotide 66 at the top of helix V does cause a destabilization of the proximal part of this helix. Also, nucleotide 109 at the top of helix V will preferentially pair with nucleotide 10 of loop A rather than nucleotide 66 when both possibilities are provided, without affecting the stability of helix V, even though the G.U pair is disrupted. The effects of these mutations on TFIIIA binding indicate that the bifurcation region is critical for protein recognition. One important feature of the relationship between 5 S rRNA structure and TFIIIA recognition resulting from this study was the observation that any mutation that constrains the bifurcation loop results in a reduced affinity of the RNA for TFIIIA, unless it is compensated for by an increased flexibility elsewhere.
J Mol Biol 1991 Mar 05
PMID:Involvement of "hinge" nucleotides of Xenopus laevis 5 S rRNA in the RNA structural organization and in the binding of transcription factor TFIIIA. 200 8

Methods for analyzing the amino-acid sequence of a protein for the purposes of predicting its three-dimensional structure were systematically analyzed using knowledge engineering techniques. The resulting entities (data) and relations (processing methods and constraints) have been represented within a generalized dependency network consisting of 29 nodes and over 100 links. It is argued that such a representation meets the requirements of knowledge-based systems in molecular biology. This network is used as the architecture for a prototype knowledge-based system that simulates logically the processes used in protein structure prediction. Although developed specifically for applications in protein structure prediction, the network architecture provides a strategy for tackling the general problem of orchestrating and integrating the diverse sources of knowledge that are characteristic of many areas of science.
J Mol Graph 1990 Jun
PMID:A knowledge-based architecture for protein sequence analysis and structure prediction. 228 57

We review briefly the general problem of assessing the similarity between one molecule and another. We propose a novel approach to the quantitative estimation of the similarity of two electron distributions. The procedure is based on momentum space concepts, and avoids many of the difficulties associated with the usual position space definitions. Results are presented for the model systems CH3CH2CH3, CH3OCH3, CH3SCH3, H2O and H2S.
J Comput Aided Mol Des 1989 Sep
PMID:A novel approach to molecular similarity. 268 76

Because the general problem of predicting the tertiary structure of a globular protein from its sequence is so difficult, researchers have tried to predict regular substructures, known as secondary structures, of proteins. Knowledge of the position of these structures in the sequence can significantly constrain the possible conformations of the protein. Traditional protein secondary structures are alpha-helices, beta-sheets, and coil. Secondary structure prediction programs have been developed, based upon several different algorithms. Such systems, despite their varied natures, are noted for their universal limit on prediction accuracy of about 65%. A possible cause for this limit is that traditional secondary structure classes are only a coarse characterization of local structure in proteins. This work presents the results of an alternative approach where local structure classes in proteins are derived using neural network and clustering techniques. These give a set of local structure categories, which we call Structural Building Blocks (SBBs), based upon the data itself, rather than a priori categories imposed upon the data. Analysis of SBBs shows that these categories are general classifications, and that they account for recognized helical and strand regions, as well as novel categories such as N- and C-caps of helices and strands.
Proc Int Conf Intell Syst Mol Biol 1993
PMID:Automatic derivation of substructures yields novel structural building blocks in globular proteins. 758 68

An interesting example of a structurally diverse group of sequentially homologous proteins is analyzed at the level of molecular interactions. In this family, the EF-hand calcium-binding proteins, there are examples of at least three distinct mutual positions of the N and C-terminal domains, despite significant sequence homology between all members of this family. Why does a particular protein choose one arrangement over another? To answer this question, detailed models of all proteins in their native structures as well as all alternative sequence/structure combinations are built by comparative modeling. By studying and comparing interactions stabilizing native structures and destabilizing alternative conformations, it is possible to gain insight into how such conformational diversity is achieved. It is shown that some mechanisms used to achieve it are: correlated mutations on the surface of two units and the presence of additional domains/chain fragments stabilizing desired topologies. The implications of these findings, both for structure predictions for other members of this family as well as the general problem of quaternary structure formation, are discussed.
J Mol Biol 1996 May 03
PMID:Structural diversity in a family of homologous proteins. 862 31

The M32L substitution mutation of staphylococcal nuclease was made to test the theoretical prediction by Yamaotsu, Moriguchi and Hirono that it would be approximately 1.6 kcal/mol more stable than the wild-type protein. Instead M32L and the closely related M32I mutant were 0.8 and 0.6 kcal/mol less stable than the wild-type protein, respectively. The theoretical treatment had successfully predicted the stability effects of other mutations in staphylococcal nuclease. The discrepancy found here may be due to a general problem of the theoretical treatment, such as inadequate molecular dynamics simulation time, or possibly due to more specific difficulty in assessing the strength of the sulfur-aromatic interaction that is present in the wild-type.
J Mol Biol 1996 Apr 05
PMID:The M32L substitution of staphylococcal nuclease: disagreement between theoretical prediction and experimental protein stability. 864 19

Instability of the mitochondrial genome (mtDNA) is a general problem from yeasts to humans. However, its genetic control is not well documented except in the yeast Saccharomyces cerevisiae. From the discovery, 50 years ago, of the petite mutants by Ephrussi and his coworkers, it has been shown that more than 100 nuclear genes directly or indirectly influence the fate of the rho(+) mtDNA. It is not surprising that mutations in genes involved in mtDNA metabolism (replication, repair, and recombination) can cause a complete loss of mtDNA (rho(0) petites) and/or lead to truncated forms (rho(-)) of this genome. However, most loss-of-function mutations which increase yeast mtDNA instability act indirectly: they lie in genes controlling functions as diverse as mitochondrial translation, ATP synthase, iron homeostasis, fatty acid metabolism, mitochondrial morphology, and so on. In a few cases it has been shown that gene overexpression increases the levels of petite mutants. Mutations in other genes are lethal in the absence of a functional mtDNA and thus convert this petite-positive yeast into a petite-negative form: petite cells cannot be recovered in these genetic contexts. Most of the data are explained if one assumes that the maintenance of the rho(+) genome depends on a centromere-like structure dispensable for the maintenance of rho(-) mtDNA and/or the function of mitochondrially encoded ATP synthase subunits, especially ATP6. In fact, the real challenge for the next 50 years will be to assemble the pieces of this puzzle by using yeast and to use complementary models, especially in strict aerobes.
Microbiol Mol Biol Rev 2000 Jun
PMID:Maintenance and integrity of the mitochondrial genome: a plethora of nuclear genes in the budding yeast. 1083 18

Both, dielectric continuum solvation models as well as surface or group based methods using polarity and lipophilicity parameters have been proven to be useful tools for the analysis of solvation and partition questions. For the first time, COSMO-RS provides an integrated theory, which combines the aspects of continuum solvation and surface interactions, and which ends up with chemical potentials of molecules in almost arbitrary solvents and mixtures. Due to its sound theoretical basis, COSMO-RS does not only provide a new quantitative access to solvation and partition properties in well defined solvents, but it also opens a novel view and gives a better understanding of the general problem of solvation. Finally, this allows for a generalisation of COSMO-RS to sophisticated physiological partition problems involving as complex phases as blood, brain, or cell membranes. The use of COSMO-RS for drug discovery and design is demonstrated by applications to blood-brain partition coefficients, and water solubility.
J Comput Aided Mol Des 2001 Apr
PMID:COSMO-RS: a novel view to physiological solvation and partition questions. 1134 17

Alzheimer's disease (AD) is a common neurodegenerative disease that affects cognitive function in the elderly. Large extracellular beta-amyloid (Abeta) plaques and tau-containing intraneuronal neurofibrillary tangles characterize AD from a histopathologic perspective. However, the severity of dementia in AD is more closely related to the degree of the associated neuronal and synaptic loss. It is not known how neurons die and synapses are lost in AD; the current review summarizes what is known about this issue. Most evidence indicates that amyloid precursor protein (APP) processing is central to the AD process. The Abeta in plaques is a metabolite of the APP that forms when an alternative (beta-secretase and then gamma-secretase) enzymatic pathway is utilized for processing. Mutations of the APP gene lead to AD by influencing APP metabolism. One leading theory is that the Abeta in plaques leads to AD because Abeta is directly toxic to the adjacent neurons. Other theories advance the notion that neuronal death is triggered by intracellular events that occur during APP processing or by extraneuronal preplaque Abeta oligomers. Some investigators speculate that in many cases there is a more general disorder of protein processing in neurons that leads to cell death. In the later models, Abeta plaques are a byproduct of the disease process, rather than the direct cause of neuronal death. A direct correlation between Abeta plaque burden and neuronal (or synaptic) loss should occur in AD if Abeta plaques cause AD through a direct toxic effect. However, histopathologic studies indicate that the correlation between Abeta plaque burden and neuronal (or synaptic) loss is poor. We conclude that APP processing and Abeta formation is important to the AD process, but that neuronal alterations that underlie symptoms of AD are not due exclusively to a direct toxic effect of the Abeta deposits that occur in plaques. A more general problem with protein processing, damage due to the neuron from accumulation of intraneuronal Abeta or extracellular, preplaque Abeta may also be important as underlying factors in the dementia of AD.
Curr Mol Med 2001 Dec
PMID:Beta-amyloid, neuronal death and Alzheimer's disease. 1189 59

Parasites sometimes expand their host range by acquiring a new host species. After a host change event, the selective regime acting on a given parasite gene may change as a result of host-specific adaptive alterations of protein functionality or host-specific immune-mediated selection. We present a codon-based model that attempts to include these effects by allowing the position-specific substitution process to change in conjunction with a host change event. Following maximum-likelihood parameter estimation, we employ an empirical Bayesian procedure to identify candidate sites potentially involved in host-specific adaptation. We discuss the applicability of the model to the more general problem of ascertaining whether the selective regime differs in two groups of related organisms. The utility of the model is illustrated on a data set of nucleoprotein sequences from the influenza A virus obtained from avian and human hosts.
Mol Biol Evol 2003 Aug
PMID:A codon-based model of host-specific selection in parasites, with an application to the influenza A virus. 1277 10


1 2 3 4 Next >>