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11.
He Y Alam SL Proteasa SV Zhang Y Lesuisse E Dancis A Stemmler TL 《Biochemistry》2004,43(51):16254-16262
The mitochondrial protein frataxin is essential for cellular regulation of iron homeostasis. Although the exact function of frataxin is not yet clear, recent reports indicate the protein binds iron and can act as a mitochondrial iron chaperone to transport Fe(II) to ferrochelatase and ISU proteins within the heme and iron-sulfur cluster biosynthetic pathways, respectively. We have determined the solution structure of apo yeast frataxin to provide a structural basis of how frataxin binds and donates iron to the ferrochelatase. While the protein's alpha-beta-sandwich structural motif is similar to that observed for human and bacterial frataxins, the yeast structure presented in this report includes the full N-terminus observed for the mature processed protein found within the mitochondrion. In addition, NMR spectroscopy was used to identify frataxin amino acids that are perturbed by the presence of iron. Conserved acidic residues in the helix 1-strand 1 protein region undergo amide chemical shift changes in the presence of Fe(II), indicating a possible iron-binding site on frataxin. NMR spectroscopy was further used to identify the intermolecular binding interface between ferrochelatase and frataxin. Ferrochelatase appears to bind to frataxin's helical plane in a manner that includes its iron-binding interface. 相似文献
12.
Kshitiz?GuptaEmail author Dina?Thomas SV?Vidya KV?VenkateshEmail author S?Ramakumar 《BMC bioinformatics》2005,6(1):105
Background
The chemical property and biological function of a protein is a direct consequence of its primary structure. Several algorithms have been developed which determine alignment and similarity of primary protein sequences. However, character based similarity cannot provide insight into the structural aspects of a protein. We present a method based on spectral similarity to compare subsequences of amino acids that behave similarly but are not aligned well by considering amino acids as mere characters. This approach finds a similarity score between sequences based on any given attribute, like hydrophobicity of amino acids, on the basis of spectral information after partial conversion to the frequency domain. 相似文献13.
Estimating synonymous and nonsynonymous substitution rates 总被引:8,自引:4,他引:4
Partitioning the total substitution rate into synnonymous and nonsynonymous
components is a key aspect of many analyses in molecular evolution.
Numerous methods exist for estimating these rates. However, until recently
none of the estimation procedures were based on a sound statistical
footing. In this paper, the evolutionary model of Muse and Gaut (1994) is
used as the basis for two sets of parameters quantifying silent and
replacement substitution rates. The parameters are shown to be equal when
the four nucleotides are equally frequent and unequal otherwise.
Maximum-likelihood estimation of these parameters is described, and the
performance of these estimates is compared to that of existing estimation
procedures. It is shown that the estimates of Nei and Gojobori (1986) are
not unbiased for either set of parameters, although they provide very good
estimates for one set as long as sequence divergence is not too high.
However, some disturbing properties are found for the Nei and Gojobori
estimates. In particular, it is shown that the expected value of the Nei
and Gojobori estimate of silent substitution rate is a function of both the
silent and replacement substitution rates. The maximum-likelihood estimates
have no such problems.
相似文献
14.
Myeloperoxidase (MPO) structural analysis has suggested that halides and pseudohalides bind to the distal binding site and serve as substrates or inhibitors, while others have concluded that there are two separate sites. Here, evidence for two distinct binding sites for halides comes from the bell-shaped effects observed when the second-order rate constant of nitric oxide (NO) binding to MPO was plotted versus Cl- concentration. The chloride level used in the X-ray structure that produced Cl- binding to the amino terminus of the helix halide binding site was insufficient to populate either of the two sites that appear to be responsible for the two phases. Biphasic effects were also observed when the I-, Br-, and SCN- concentrations were plotted against the NO combination rate constants. Interestingly, the trough concentrations obtained from the bell-shaped curves are comparable to normal plasma levels of halides and pseudohalides, suggesting the potential relevance of these molecules in modulating MPO function. The second-order rate constant of NO binding in the presence of plasma levels of I-, Br-, and SCN- is 1-2-fold lower compared to that obtained in the absence of these molecules and remains unaltered through the Cl- plasma level. When Cl- exceeded the plasma level, the NO combination rate becomes indistinguishable from the second phase of the bell-shaped curve that was obtained in the absence of halides. Our results are consistent with two halide binding sites that could be populated by two halides in which both display distinct effects on the MPO heme iron microenvironment. 相似文献
15.
A nearly universal feature of intron sequences is that even closely related
species exhibit a large number of insertion/deletion differences. The goal
of the analysis described here is to test whether the observed pattern of
insertion/deletion events in the genealogy of the myosin alkali light chain
(Mlc1) gene is consistent with neutrality, and if not, to determine the
underlying forces of evolutionary change. Mlc1 pre-mRNA is alternatively
spliced, and one constraint is that signals necessary for
tissue-specificity of directed splicing must be conserved. If the total
length of an intron is functionally constrained, then the distribution of
indels on branches of the gene genealogy should reflect a departure from
randomness. Here we perform a phylogenetic analysis, inferring ancestral
states wherever possible on a phylogeny of 29 alleles of Mlc1 from six
species of Drosophila. Observed patterns of indels on the genealogy were
compared to those from simulated data, with the result that we cannot
reject the null hypothesis of neutrality. A clear departure from a neutral
prediction was seen in the excess folding free energy predicted for the
introns flanking the alternatively spliced exon. Relative rate tests also
suggest a retardation in the rate of Mlc1 sequence evolution in the
simulans clade.
相似文献
16.
A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome 总被引:29,自引:24,他引:5
A model of DNA sequence evolution applicable to coding regions is
presented. This represents the first evolutionary model that accounts for
dependencies among nucleotides within a codon. The model uses the codon, as
opposed to the nucleotide, as the unit of evolution, and is parameterized
in terms of synonymous and nonsynonymous nucleotide substitution rates. One
of the model's advantages over those used in methods for estimating
synonymous and nonsynonymous substitution rates is that it completely
corrects for multiple hits at a codon, rather than taking a parsimony
approach and considering only pathways of minimum change between homologous
codons. Likelihood-ratio versions of the relative-rate test are constructed
and applied to data from the complete chloroplast DNA sequences of Oryza
sativa, Nicotiana tabacum, and Marchantia polymorpha. Results of these
tests confirm previous findings that substitution rates in the chloroplast
genome are subject to both lineage-specific and locus-specific effects.
Additionally, the new tests suggest tha the rate heterogeneity is due
primarily to differences in nonsynonymous substitution rates. Simulations
help confirm previous suggestions that silent sites are saturated, leaving
no evidence of heterogeneity in synonymous substitution rates.
相似文献
17.
ALEKSANDRA I. JOHANSEN ALICE EXNEROVÁ KATEŘINA HOTOVÁ SVÁDOVÁ PAVEL ŠTYS GABRIELLA GAMBERALE‐STILLE BIRGITTA S. TULLBERG 《Ecological Entomology》2010,35(5):602-610
1. Protective coloration in insects may be aposematic or cryptic, and some species change defensive strategy between instars. In Sweden, the adult striated shieldbugs Graphosoma lineatum (Heteroptera: Pentatomidae) undergo a seasonal colour change from pale brown and black striation in the pre‐hibernating adults, to red and black striation in the same post‐hibernating individuals. To the human eye the pre‐hibernating adults appear cryptic against the withered late summer vegetation, whereas the red and black post‐hibernating adults appear aposematic. This suggests a possibility of a functional colour change. However, what is cryptic to the human eye is not necessarily cryptic to a potential predator. 2. Therefore we tested the effect of coloration in adult G. lineatum on their detectability for avian predators. Great tits (Parus major) were trained to eat sunflower seeds hidden inside the emptied exoskeletons of pale or red G. lineatum. Then the detection time for both colour forms was measured in a dry vegetation environment. 3. The birds required a longer time to find the pale form of G. lineatum than the red one. The pale form appears more cryptic on withered late summer vegetation than the red form, not only to the human eye but also to avian predators. The result supports the idea that the adult individuals of G. lineatum undergo a functional change from a cryptic protective coloration to an aposematic one. 相似文献
18.
Martin P Vickrey JF Proteasa G Jimenez YL Wawrzak Z Winters MA Merigan TC Kovari LC 《Structure (London, England : 1993)》2005,13(12):1887-1895
This report examines structural changes in a highly mutated, clinical multidrug-resistant HIV-1 protease, and the crystal structure has been solved to 1.3 A resolution in the absence of any inhibitor. This protease variant contains codon mutations at positions 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90 that confer resistance to protease inhibitors. Major differences between the wild-type and the variant include a structural change initiated by the M36V mutation and amplified by additional mutations in the flaps of the protease, resulting in a "wide-open" structure that represents an opening that is 8 A wider than the "open" structure of the wild-type protease. A second structural change is triggered by the L90M mutation that results in reshaping the 23-32 segment. A third key structural change of the protease is due to the mutations from longer to shorter amino acid side chains at positions 82 and 84. 相似文献
19.
Vickrey JF Logsdon BC Proteasa G Palmer S Winters MA Merigan TC Kovari LC 《Protein expression and purification》2003,28(1):165-172
High-resolution X-ray crystallographic structures of HIV-1 protease clinical variants complexed with licensed inhibitors are essential to understanding the fundamental cause of protease drug resistance. There is a need for structures of naturally evolved HIV-1 proteases from patients failing antiretroviral therapy. Here, we report the expression, purification, and crystallization of clinical isolates of HIV-1 protease that have been characterized to be more than 100 times less susceptible to US FDA approved protease inhibitors. 相似文献
20.
Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity
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Logsdon BC Vickrey JF Martin P Proteasa G Koepke JI Terlecky SR Wawrzak Z Winters MA Merigan TC Kovari LC 《Journal of virology》2004,78(6):3123-3132
The goal of this study was to use X-ray crystallography to investigate the structural basis of resistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors. We overexpressed, purified, and crystallized a multidrug-resistant (MDR) HIV-1 protease enzyme derived from a patient failing on several protease inhibitor-containing regimens. This HIV-1 variant contained codon mutations at positions 10, 36, 46, 54, 63, 71, 82, 84, and 90 that confer drug resistance to protease inhibitors. The 1.8-angstrom (A) crystal structure of this MDR patient isolate reveals an expanded active-site cavity. The active-site expansion includes position 82 and 84 mutations due to the alterations in the amino acid side chains from longer to shorter (e.g., V82A and I84V). The MDR isolate 769 protease "flaps" stay open wider, and the difference in the flap tip distances in the MDR 769 variant is 12 A. The MDR 769 protease crystal complexes with lopinavir and DMP450 reveal completely different binding modes. The network of interactions between the ligands and the MDR 769 protease is completely different from that seen with the wild-type protease-ligand complexes. The water molecule-forming hydrogen bonds bridging between the two flaps and either the substrate or the peptide-based inhibitor are lacking in the MDR 769 clinical isolate. The S1, S1', S3, and S3' pockets show expansion and conformational change. Surface plasmon resonance measurements with the MDR 769 protease indicate higher k(off) rates, resulting in a change of binding affinity. Surface plasmon resonance measurements provide k(on) and k(off) data (K(d) = k(off)/k(on)) to measure binding of the multidrug-resistant protease to various ligands. This MDR 769 protease represents a new antiviral target, presenting the possibility of designing novel inhibitors with activity against the open and expanded protease forms. 相似文献