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PubMed1975

[Patho-anatomical characteristics of renal cell cancer].

A total of 61 observations on nephrocellular cancer were carried out. It was established that the tumour was not uniform by its histological structure neither in the primary node nor in metastases. Four variants of a histological structure of the cancer were identified: clear-cell, granular, sarcoma-like, and grandular. The one-type histological structure (one variant) in the primary node and in the most common metastases was identified nearly with the same frequency--in 60-66% of the cases. In the rest of the cases the tumour was of a mixed structure; more often there were observed combinations of 2 variants and more seldom--of 3 or 4 combinations. As a rule, metastases histologically corresponded to the primary node, but had peculiar features of their own depending on their localization. Divercity of morphological structures of tumours should be born in mind in making the histological diagnosis of nephrocellular cancer, partitularly if the volume of tissues obtained is small.

Adenocarcinoma↗
PubMed1993

Human glucose-6-phosphate dehydrogenase: structure and function of normal and variant enzymes.

Glucose-6-phosphate dehydrogenase (G6PD) is a unique enzyme with many genetic variants. Recent progress in molecular biological techniques have provided several important findings about the structure-function relationship of human G6PD. A putative substrate glucose-6-phosphate binding (around Lys 205) and a putative 'structural' NADP binding site (around Lys 386) have been identified. A conservative segment (amino acid 38-44) near the N-terminus was proposed to be the possible second NADP binding region (amino acid 38-44). Analysis of amino acid substitutions of variants revealed that there might be some relationship between the position of substitution and the properties of variants.

Amino Acid Sequence↗
PubMed2000

Mechanisms for the enhanced thermal stability of a mutant of transcription factor 1 as explained by (1)H, (15)N and (13)C NMR chemical shifts and secondary structure analysis.

A variant of the bacteriophage SPO1-encoded transcription factor 1 (TF1) with two site-specific mutations (E15G and T32I) was shown to be more thermally stable and bind DNA more tightly compared to the wild-type protein. In order to understand the biochemical mechanisms underlying these properties, we are engaged in determining the solution structures of this mutant alone and in complex with DNA using nuclear magnetic resonance (NMR) spectroscopy. The first phase of this project is reported here, as we have completed most of the backbone and sidechain sequential NMR assignments of the mutant protein, TF1-G15/I32. Insights derived from the (1)H, (15)N and (13)C chemical shifts and from the secondary structure analysis provide us with an explanation for the noted increase in thermal stability of TF1-G15/I32. Compared to the structure of the wild-type protein, the beta-sheet and the C-terminal helix remain largely unaffected whereas the mutations cause great changes in the first two helices and their enclosed loop. Specifically, we have found that the second helix is extended by one residue at its N-terminus and rotated in a way that allows Ala-37 to interact with Tyr-94 of the C-terminal helix. The loop has been found to become more rigid as a result of hydrophobic interactions between the flanking second and first helices and also between the second helix and the loop itself. Furthermore, the T32I mutation allows tighter packing between the second helix and the beta-sheet. Collectively, these changes contribute to a more tightly associated dimer and hence, to a greater thermal stability.

DNA-Binding Proteins↗
PubMed2001

Nb4Pd0.5ZSb2 (Z = Cr, Fe, Co, Ni, Si): the first ordered quaternary variants of the W5Si3-type structure.

A family of quaternary (or pseudoquaternary) antimonides Nb4Pd0.5ZSb2 (Z = Cr, Fe, Co, Ni, Si) containing up to three transition metals in an ordered arrangement has been prepared by reactions of the elements. These antimonides are isostructural, crystallizing as substitutional variants of the W5Si3-type structure (tetragonal, space group -I4/mcm, Z = 4) with unit cell parameters a = 10.4407(3) A and c = 5.0020(2) A for Nb4Pd0.5Cr0.28(3)Si0.72Sb2, a = 10.4825(6) A and c = 4.9543(3) A for Nb4Pd0.5FeSb2, a = 10.4603(5) A and c = 4.9457(3) A for Nb4Pd0.5CoSb2, a = 10.4332(7) A and c = 4.9649(3) A for Nb4Pd0.5Ni0.78(1)Sb2, and a = 10.3895(10) A and c = 4.9634(4) A for Nb4Pd0.5SiSb2. They are distinguished by the filling of interstitial Z atoms into the centers of Nb8 square antiprismatic clusters that are linked by PdSb4 tetrahedra. The Nb8 square antiprisms share opposite square faces to form one-dimensional chains along the c axis so that Z-Z bonding distances of approximately 2.5 A result. Extended Hückel band structure calculations were carried out to interpret the homo- and heteroatomic metal-metal interactions in the structure. The resistivity of one member, Nb4Pd0.5SiSb2, was measured, indicating metallic behavior.

Journal Article↗
PubMed1996

Perturbations in the surface structure of A22 Iraq foot-and-mouth disease virus accompanying coupled changes in host cell specificity and antigenicity.

BACKGROUND: Foot-and-mouth disease virus (FMDV) is an extremely infectious and antigenically diverse picornavirus of cloven-hoofed animals. Strains of the A22 subtype have been reported to change antigenically when adapted to different growth conditions. To investigate the structural basis of this phenomenon we have determined the structures of two variants of an A22 virus. RESULTS: The structures of monolayer- and suspension-cell-adapted A22 FMDV have been determined by X-ray crystallography. Picornaviruses comprise four capsid proteins, VP1-4. The major antigenic loop of the capsid protein VP1 is flexible in both variants of the A22 subtype but its overall disposition is distinct from that observed in other FMDV serotypes (O and C). A detailed structural comparison between A22 FMDV and a type O virus suggests that different conformations in a portion of the major antigenic loop of VP1 (the GH loop, which is also central to receptor attachment) result in distinct folds of the adjacent VP3 GH loop. Also, a single mutation (Glu82-->Gly) on the surface of VP2 in the suspension-cell-adapted virus appears to perturb the structure of the VP1 GH loop. CONCLUSION: The GH loop of VP1 is flexible in three serotypes of FMDV, suggesting that flexibility is important in both antigenic variability and structural communication with other regions of the virus capsid. Our results illustrate two instances of the propagation of structural perturbations across the virion surface: the change in the VP3 GH loop caused by the VP1 GH loop and the Glu82-->Gly change in VP2 which we believe perturbs the GH loop of VP1. In the latter case, the amplification of the sequence changes leads to differences, between the monolayer- and suspension-cell-adapted viruses, in host-cell interactions and antigenicity.

Antigens, Viral↗
PubMed1990

Structural difference of chymotrypsinogens forming chymotrypsin variants in Japanese quail.

A chymotrypsinogen showing the phenotype AA of chymotrypsin was purified from quail pancreas, and its chromatographic behavior, molecular weight, and electrophoretic mobility were very similar to those of another chymotrypsinogen, showing the aa phenotype of chymotrypsin. However, after activation, this chymotrypsinogen from AA showed band 5 of chymotrypsin, while the other chymotrypsinogen from aa did not. Peptide mapping demonstrated that the molecular structures of the two chymotrypsinogens are different. It was recognized that chymotrypsin variants result from activated products of different molecular structures of chymotrypsinogens.

Animals↗
PubMed1977

Structural studies of the Shigella flexneri variant X, type 5 a and type 5 b O-antigens.

Previous studies of different Shigella flexneri O-antigens indicate that their O-specific region is composed of oligosaccharide repeating units containing a basic tetrasaccharide structure, to which alpha-D-glucopyranosyl groups and O-acetyl groups may be attached to different positions. Structural studies of O-antigens from variant X, type 5a and type 5b lend further support to this assumption. These antigens contain terminal alpha-D-glucopyranosyl groups, one each per repeating unit in X and 5a, two in 5b. The location of these groups in the repeating unit has been determined.

Carbohydrates↗
PubMed1983

Determinants recognized by murine rheumatoid factors: molecular localization using a panel of mouse myeloma variant immunoglobulins.

The structures recognized by monoclonal anti-IgG1 rheumatoid factors (RF) were localized by testing their reactivity with mutant immunoglobulins carrying gamma 1 chains that lacked either the CH1 or the CH3 domains. While optimal binding was observed in the absence of CH1, deletion of CH3 completely abolished the reactivity of all but one of the 71 monoclonal RF tested. Similar experiments were carried out with IgG2a- and IgG2b-specific RF by using variant immunoglobulins carrying various hybrid gamma 2a-gamma 2b heavy chains. It was found that both the polyclonal RF produced by autoimmune strains, MRL/MpJ-lpr and NZB/BinJ, and most of the monoclonal RF derived from normal strains, BALB/c, C57Bl/6, and 129/Sv, were directed against determinants located in a segment spanning the C-terminal 8 residues of the CH2 domain and the complete CH3 domain.

Animals↗
PubMed2006

Insights into the role of nucleotide-dependent conformational change in nitrogenase catalysis: Structural characterization of the nitrogenase Fe protein Leu127 deletion variant with bound MgATP.

In the present work, determination of the structure of the nitrogenase Leu 127 deletion variant Fe protein with MgATP bound is presented, along with density functional theory calculations, to provide insights into the roles of MgATP in the nitrogenase reaction mechanism. Comparison of the MgATP-bound structure of this Fe protein to the nucleotide-free form indicates that the binding of MgATP does not alter the overall structure of the variant significantly with only small differences in the conformation of amino acids in direct contact with the two bound MgATP molecules being seen. The earlier observation of splitting of the [4Fe-4S] cluster into two [2Fe-2S] clusters was observed to be unaltered upon binding MgATP. Density functional theory was used to probe the assignment of ligands to the two [2Fe-2S] rhombs. The Mg(2+) environment in the MgATP-bound structure of the Leu127 deletion Fe protein is similar to that observed for the Fe protein in the nitrogenase Fe protein: MoFe protein complex stabilized by MgADP and tetrafluoroaluminate suggesting that large scale conformational change implicated for the Fe protein may not be mediated by changes in the Mg(2+) coordination. The results presented here indicated that MgATP may enhance the stability of an open conformation and prohibit intersubunit interactions, which have been implicated in promoting nucleotide hydrolysis. This could be critical to the tight control of MgATP hydrolysis observed within the nitrogenase complex and may be important for maintaining unidirectional electron flow toward substrate reduction.

Adenosine Triphosphate↗
PubMed1985

Structural analysis of an HLA-B27 functional variant: identification of residues that contribute to the specificity of recognition by cytolytic T lymphocytes.

The structure of a variant HLA-B27 antigen, B27.2, that is distinguished from the HLA-B27.1 and HLA-B27.3 subgroups by specific cytolytic T lymphocytes has been established by comparative peptide mapping and sequence analysis. There are only three amino acid substitutions between B27.1 and B27.2: aspartate-77, threonine-80, and leucine-81 in HLA-B27.1 are changed to asparagine-77, isoleucine-80, and alanine-81 in HLA-B27.2. These changes account for their single charge difference detectable by isoelectric focusing. The three clustered substitutions of HLA-B27.2 are identical to the corresponding residues in HLA-A24, so that both molecules become identical in their amino acid sequence between residues 72 and 96. This suggests that gene conversion may have occurred during the diversification of the HLA-B27 antigens. HLA-B27.2 has no changes in the alpha 2 domain and is similar in its pattern of substitutions to the murine bm11 mutant. It is suggested that residues 77-81 are of major significance in determining the specificity of cellular recognition of class I HLA antigens. This study, together with the previous analyses of HLA-B27.1 and HLA-B27.3, completes the structural characterization of the three major HLA-B27 functional subtypes and establishes the molecular basis of their functional and serological differences.

Amino Acid Sequence↗
PubMed2006

Structures of the dimeric and monomeric variants of magainin antimicrobial peptides (MSI-78 and MSI-594) in micelles and bilayers, determined by NMR spectroscopy.

Magainins are antimicrobial peptides that selectively disrupt bacterial cell membranes. In an effort to determine the propensity for oligomerization of specific highly active magainin analogues in membrane mimetic systems, we studied the structures and lipid interactions of two synthetic variants of magainins (MSI-78 and MSI-594) originally designed by Genaera Corp. Using NMR experiments on these peptides solubilized in dodecylphosphocholine (DPC) micelles, we found that the first analogue, MSI-78, forms an antiparallel dimer with a "phenylalanine zipper" holding together two highly helical protomers, whereas the second analogue, MSI-594, whose phenylalanines 12 and 16 were changed into glycine and valine, respectively, does not dimerize under our experimental conditions. In addition, magic angle spinning solid-state NMR experiments carried out on multilamellar vesicles were used to corroborate the helical conformation of the peptides found in detergent micelles and support the existence of a more compact structure for MSI-78 and a pronounced conformational heterogeneity for MSI-594. Since magainin activity is modulated by oligomerization within the membrane bilayers, this study represents a step forward in understanding the role of self-association in determining magainin function.

Amino Acid Sequence↗
PubMed1983

Comparative structural analysis of HLA-A2 antigens distinguishable by cytotoxic T lymphocytes. II. Variant DK1: evidence for a discrete CTL recognition region.

Multiple amino acid sequence differences distinguish individual HLA antigens. Those residues important in immune recognition events have not been defined. Recent studies have identified HLA-A2 structural variants that, although serologically indistinguishable from other HLA-A2 antigens, are recognized poorly, if at all, by HLA-A2-restricted, influenza virus-immune, or HLA-A2-specific alloimmune CTL. In this study we utilize double-label tryptic peptide comparisons performed by both reverse-phase HPLC and cation exchange chromatography, in conjunction with conventional and microsequence analysis, to characterize the HLA-A2 heavy chains derived from variant DK1. We detect a single tryptic peptide that distinguishes DK1 HLA-A2 from the predominant HLA-A2 heavy chain species. This peptide spans residues 147 to 157 in the second heavy chain domain, and carries substitutions at positions 149, 152, and 156. Residues in this segment of the polypeptide are also altered in another HLA-A2 variant, as well as one H-2Kb mutant. Thus, this segment appears to be critical in forming determinants important in CTL recognition of class I antigens in general. On the basis of these and other results, we suggest that in contrast to recognition by alloantibodies, a discrete region of class I antigens may be crucial for CTL recognition.

Amino Acid Sequence↗
PubMed1981

Genome structure of Abelson murine leukemia virus variants: proviruses in fibroblasts and lymphoid cells.

We have prepared full-length DNA clones of the Abelson murine leukemia virus (A-MuLV) genome. A specific probe homologous to the central portion of the A-MuLV genome was prepared by nick translation of a subcloned restriction fraction from the cloned DNA. The probe was used to examine the genome structure of several A-MuLV variants. The conclusions are: (i) three viruses coding for Abelson-specific proteins of molecular weight 120,000, 100,000, and 90,000 had genomes indistinguishable in size, suggesting that the shorter proteins are the result of early translational termination; (ii) compared with the genome encoding the 120,000-dalton (120K) protein, a genome coding for a 160K protein was 0.8 kilobase larger in the A-MuLV-specific region; and (iii) a genome coding for a 92K protein had a 700-base pair deletion internal to the coding region. This mutant was transformation defective: its 92K protein lacked the protein kinase activity normally associated with the A-MuLV protein, and cells containing the virus were not morphologically transformed. In addition, we determined the number of A-MuLV proviruses in each of several transformed fibroblast and lymphoid cells prepared by infection in vitro. These experiments show that a single copy of the A-MuLV provirus is sufficient to transform both types of cells and that nonproducer cells generally have only one integrated provirus.

Abelson murine leukemia virus↗
PubMed1991

Hemoglobin Terre Haute arginine beta 106. A posthumous correction to the original structure of hemoglobin Indianapolis.

The initial report of Hb Indianapolis described two affected individuals with the phenotype of severe beta-thalassemia that was dominantly inherited. The structure of this variant could not be deduced by standard techniques because of its extreme instability. Because of this limitation, the structure was ascertained by analysis of the abnormal globin chain, which had been radioactively labeled. These studies strongly suggested that the structure of this variant was cysteine beta 112 to arginine. Subsequent to this report, two additional families with Hb Indianapolis were found. The carriers were minimally affected and the abnormal hemoglobin was only mildly unstable. This major difference in phenotypic expression suggested that further investigation of the original family should be carried out. Unfortunately, both of the original carriers of the variant succumbed to their severe anemia prior to the subsequent reports. However, by the use of the polymerase chain reaction, enough DNA was obtained to sequence the third exon of the beta-globin gene in the original family from the DNA scraped off a 10-year-old bone marrow microscope slide. These studies revealed a substitution of leucine to arginine at position 106 of the beta-globin chain. The polymerase chain reaction results may be consistent with the original protein structural data, if incomplete tryptic cleavage of this arginine residue occurred in the original sample. We have renamed this variant Hb Terre Haute in an attempt to avoid confusion with the Cys beta 112----Arg substitution.

Arginine↗
PubMed2001

Two variants of the Drosophila melanogaster retrotransposon gypsy (mdg4): structural and functional differences, and distribution in fly stocks.

Two variants of the Drosophila melanogaster retrotransposon gypsy were subjected to detailed structural and functional analysis. A series of hybrid constructs containing various combinations of "active" and "inactive" gypsy copies were tested for their ability to produce new DNA copies in cultured cells by means of reverse transcription. It was shown that the previously demonstrated variations in retrotranspositional activity are associated with either one or both of two amino acid substitutions at the beginning of ORF2. The first substitution is located at the boundary between the putative protease and reverse transcriptase domains and, hence, may influence the processing of the polyprotein. The other substitution may alter reverse transcriptase activity since it is located in the second of the seven conserved domains of the RT gene. To address the question of the evolutionary relationship between the two gypsy variants, their distribution was analyzed in among various fly stocks. Southern analysis revealed that all D. melanogaster strains studied so far contain the "inactive" gypsy variant, while the "active" copies are present only in some strains; most of the latter were established from flies recently isolated from natural populations. Finally, in stocks carrying the flamenco mutation the "active" gypsy variant is much more abundant than the "inactive" form. Possible scenarios for the orgin of the "active" form of gypsy are discussed.

Animals↗
PubMed2001

Psychomotor EEG variant of Gibbs: an association with underlying structural pathology.

OBJECTIVE: To describe the association between a unilateral mid-temporal rhythmic theta discharge ("psychomotor variant of Gibbs") with neuroimaging-demonstrated underlying mass lesion. METHODS: Standard routine awake and scalp electroencephalography, continuous video-EEG monitoring and magnetic resonance brain imaging were employed in the diagnostic work-up of a 9-year-old boy with a severe behavioural disturbance and episodic outbursts of aggression. RESULTS: EEG showed a unilateral mid-temporal rhythmic discharge which was continuous in drowsiness and which remained confined to the right hemisphere. MRI showed a lesion in the temporal horn of the right lateral ventricle displacing superiorly the white matter stem of the right temporal lobe. CONCLUSION: A rhythmic mid-temporal theta discharge, commonly regarded as a benign EEG variant, may, in some patients, reflect underlying structural pathology. Neuroimaging should be considered particularly when this EEG pattern remains confined to one hemisphere.

Brain Diseases↗
PubMed2001

Assignment of EPR Transitions in a Manganese-Containing Lipoxygenase and Prediction of Local Structure.

A new variant of lipoxygenases, one containing manganese instead of iron, is characterized by electron paramagnetic resonance (EPR) at two frequencies. In the manganous state (S(e) = 5/2), maganese lipoxygenase (MnLO) yields very broad X-band (9.2 GHz) EPR signals, extending over about 800 mT. In contrast, at W-band (94 GHz), the signal is much simplified, consisting of nested transitions centered near the free electron g-value. Computer simulation has been employed to derive estimates of the zero-field splittings for MnLO, with data from these two EPR frequencies. The general features of both X- and W-band spectra are fit, first, by simulations with S(e) = 5/2, but no nuclear hyperfine splitting. The simulations are then refined by inclusion of the hyperfine splitting. On the basis of the simulations, the ranges of zero-field splitting parameters are D = +0.07 to +0.10 cm(-1), and E/D = 0.13 to 0.23. Comparison of the value of D for MnLO with that of other manganese-containing proteins suggests that MnLO has three N-ligands to the metal center and O-ligands in the remainder of 6 coordination positions. The coordination environment of MnLO is similar to that in iron lipoxygenases.

Journal Article↗
PubMed2006

Structure-based design of a FAAH variant that discriminates between the N-acyl ethanolamine and taurine families of signaling lipids.

Fatty acid amide hydrolase (FAAH) inactivates a large and diverse class of endogenous signaling lipids termed fatty acid amides. Representative fatty acid amides include the N-acyl ethanolamines (NAEs) anandamide, which serves as an endogenous ligand for cannabinoid receptors, and N-oleoyl and N-palmitoyl ethanolamine, which produce satiety and anti-inflammatory effects, respectively. Global metabolite profiling studies of FAAH (-/-) mice have recently identified a second class of endogenous FAAH substrates: the N-acyl taurines (NATs). To determine the metabolic and signaling functions performed by NAEs and NATs in vivo, a FAAH variant that discriminates between these two substrate classes would be of value. Here, we report the structure-guided design of a point mutant in the active site of FAAH that selectively disrupts interactions with NATs. This glycine-to-aspartate (G268D) mutant was found to exhibit wild-type kinetic parameters with NAEs, but more than a 100-fold reduction in activity with NATs attributable to combined effects on Km and kcat values. These in vitro properties were also observed in living cells, where WT-FAAH and the G268D mutant displayed equivalent hydrolytic activity with NAEs, but the latter enzyme was severely impaired in its ability to catabolize NATs. The G268D FAAH mutant may thus serve as a valuable research tool to illuminate the unique roles played by the NAE and NAT classes of signaling lipids in vivo.

Amidohydrolases↗