Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Human hereditary diseases such as xeroderma pigmentosum, Fanconi's anemia, ataxia telangiectasia, and Bloom's syndrome are characterized by a proneness for developing cancer associated with abnormalities in the processing of DNA damage. The molecular defects responsible for predisposing human tissues to cancer are still not well understood, despite the fact that a considerable amount of work has already been done on this problem. In this paper, we show that in human tumor cell lines, in cells transformed by DNA tumor viruses, and in cells derived from certain cancer-prone disorders, the level of activity of a 42-kDa deoxyribonuclease is many times higher than in diploid untransformed control cells. This suggests that this activity is linked to, or may play a role in, malignant transformation.
Mol Carcinog 1989
PMID:Enhanced deoxyribonuclease activity in human transformed cells and in Bloom's syndrome cells. 280 19

This study reports the fate of hairless mouse epidermal basal cells arrested in mitosis by a traditional stathmokinetic dose of 0.15 mg Colcemid. Epidermal basal cells in the S phase were labeled with 30 microCi (3H)TdR i.p. After 1 h, four animals from a cage of eight mice were given 0.15 mg Colcemid (Fluka) in 0.5 ml saline, and the other four mice were given saline only. Groups of eight mice (four experimental, four controls) were sacrificed 4, 9, 13, 21 and 25 h after (3H)TdR injection (i.e. 3, 8, 12, 16, 20 and 24 h after Colcemid). The following cell kinetic parameters were determined: the number of labeled basal and suprabasal cells, the mean grain count of the labeled cells, the specific activity, the mitotic count, the number of labeled mitoses, the fraction of labeled mitoses curve and the fraction of cells in S and in G2 as determined by flow cytometry. "Labeled paired twins", i.e. adjoining labeled cells with approximately the same grain count, were also scored. All the results taken together support the conclusion that cells labeled with (3H)TdR and arrested 1 h later with 0.15 mg Colcemid go through at least one subsequent cell division and thereafter some of them move out into the suprabasal layer at a normal rate. Hence, after this dose of Colcemid, cells arrested in mitosis for some hours do not die, and the Colcemid treatment does not seem to produce hyperploid cells. The study confirms the usefulness of this dose of Colcemid as a convenient tool for cell kinetic studies.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:The fate of epidermal colcemid-arrested mitoses. 287 76

Of the six cubic phases identified so far in lipid-containing systems, the structures of only two have been determined unambiguously. We tackle the structure determination of the other four. We use for that purpose a novel pattern recognition approach, which consists of generating all the sets of phase angles (phi-sets) compatible with the observed reflections, and of screening them in a search for the "best" one. Two criteria are used for screening: both involve the parameter [(delta rho)4] (delta rho is a dimensionless function proportional to the Fourier transform of the set of observed structure factors). One is a test of smoothness, based upon the postulate that the "best" phi-set is that whose [(delta rho)4] is minimum; this criterion, equivalent to maximum entropy, is fulfilled when the system is devoid of heavy atoms, and when the polar and the hydrocarbon moieties occupy almost equal volumes. The other criterion is based upon the notion that [(delta rho)4] takes the same (or similar) values in thermodynamic phases with the same (or similar) chemical composition, whatever the structure of the phases. The validity of the two criteria is verified using numerous examples. The six cubic phases are analysed using this approach. The structure of three of them (Q230, Q224, Q229) can be described in terms of two three-dimensional networks of connected rods, mutually intertwined and unconnected: in Q230 the rods are coplanarly joined 3 by 3; in Q224 the rods are tetrahedrally joined 4 by 4; in Q229 the rods are cubically joined 6 by 6. The structures of Q212 and Q227 are related to those of Q230 and Q224, respectively; one of the two networks of rods is preserved, the other is replaced by a lattice of closed micelles. The structure of Q223 appears to consist of a cage-like continuous three-dimensional network of connected globules, coplanarly joined 3 by 3 at one end and 4 by 4 at the other, enclosing a three-dimensional lattice of closed micelles. The analogies of the structures of Q230, Q224, Q229 with the three fundamental cubic infinite periodic minimal surfaces are discussed. More interestingly, the structures of, on the one hand Q230, Q224, Q229 and of Q212, Q227, Q223 on the other, are shown to provide topological generalizations of the two paradigms of lipid organization; namely, the bilayer and the monolayer.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1988 Nov 05
PMID:Cubic phases of lipid-containing systems. Structure analysis and biological implications. 321 91

t- Butylbicyclophosphorothionate ( TBPS ), a derivative of potent GABA antagonistic cage convulsants, has recently been introduced ( Squires , R. F., J.E. Casida , M. Richardson, and E. Saederup (1983) Mol. Pharmacol. 13:326-336) as ligand for a GABA-A receptor-linked drug receptor. Using conventionally prepared washed membrane fractions from rat cerebral cortex, we have confirmed that in the presence of 200 mM NaBr [35S] TBPS binds to a high affinity population of binding sites (Kd 26 +/- 5 nM) and that muscimol inhibits [35S] TBPS binding (IC50 0.32 microM) allosterically. In 200 mM NaCl the apparent affinity of [35S] TBPS binding sites is lower (Kd 60 +/- 5 nM), and muscimol has biphasic effects with stimulation at low concentrations of muscimol (EC50 0.023 microM) followed by inhibition at high concentrations (IC50 0.72 microM). Both base line [35S] TBPS binding (in 200 mM NaCl) and muscimol inhibition of [35S] TBPS binding (in 200 mM NaBr) are bidirectionally modulated by the occupancy of benzodiazepine receptors with its ligands. Benzodiazepine receptor agonists, regardless of their structure, enhance and inverse benzodiazepine receptor agonists inhibit base line [35S] TBPS binding and muscimol inhibition of [35S] TBPS binding. Fourteen ligands for benzodiazepine receptors display a similar in vitro profile as benzodiazepine receptor agonists or inverse benzodiazepine receptor agonists on [35S] TBPS binding as their anti- or proconvulsive effects in vivo suggest (Jensen, L. H., E. N. Petersen, and C. Braestrup (1983) Life Sci. 33: 393-399). That [35S] TBPS binding sites are constituents of a GABA benzodiazepine receptor complex is also suggested by a number of membrane pretreatments.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[35S]-t-butylbicyclophosphorothionate binding sites are constituents of the gamma-aminobutyric acid benzodiazepine receptor complex. 632 34

The X-ray structures of the 1:1 complexes formed between p21H-ras (residues 1 to 166) and the nucleotides P3-1-(2-nitrophenyl)ethyl guanosine triphosphate ("caged GTP"; pure R- and S-diastereomers) and 3'-O-(N-methylanthraniloyl)-2'-deoxyguanosine 5'-(beta, gamma-imido)-triphosphate ("mant dG-ppNHp"), have been refined to an R-factor of 21.4% (R-caged GTP, 1.85 A resolution), 18.9% (S-caged GTP, 2.5 A resolution) and 17.6% (mant dGppNHp, 2.7 A resolution), respectively. Details of the structure determination, refinement and the structures themselves are presented. The overall structures of the complexes are identical in terms of the general organization of their secondary structure elements and are also identical to that reported for the analogous complex of p21H-ras with GppNHp. The binding of the GTP part is not significantly affected by the additional aromatic group (cage and mant, respectively) in contrast to the original observation on p21:caged GTP using the racemic mixture of R- and S-caged GTP. The main differences in the structures are observed in the region of loop L2 (residues Glu31 to Thr35) where the additional aromatic group attached to the nucleotide comes very close to the side-chain of Tyr32, including backbone displacements of 2.6 A, 2.2 A and 0.3 A for the residues from Glu31 to Thr35 for R-caged, S-caged GTP and mant dGppNHp, respectively. The refined structures provide additional data for the design of new nucleotide analogs and the importance of their stereochemistry as well as for the design of new mutant forms of p21H-ras for further biochemical investigations. The binding mode of mant dGppNHp reveals significant features for the understanding of the fluorescence signals observed in solution.
J Mol Biol 1995 Oct 13
PMID:X-ray crystal structure analysis of the catalytic domain of the oncogene product p21H-ras complexed with caged GTP and mant dGppNHp. 747 8

RNase P in both prokaryotes and eukaryotes is a ribonucleoprotein that cleaves tRNA precursors to generate the 5' termini of the mature tRNAs. Many patients with autoimmune diseases produce antibodies against a 40 kDa protein (designated To or Th antigen) which is an integral component of eukaryotic RNaseP as well as nucleolar 7-2 RNP which is identical to the mitochondrial RNA processing (MRP) RNP. Interestingly, the To antigen found in human cells and the C5 protein, the only protein component of E. coli RNaseP, are antigenically related. In this study, we show that a 56 nucleotide-long sequence, corresponding to nucleotides 20-75 near the 5' end of human RNaseP RNA, is sufficient to bind the To antigen. We previously showed that the human To antigen binds to a short distinct structural domain near the 5' end of human 7-2/MRP RNA. There is no obvious primary sequence homology between the To antigen binding sites in RNaseP RNA and 7-2/MRP RNA; however, these sequences are capable of assuming a similar secondary structure which corresponds to the recently proposed 'cage' structure for RNaseP RNAs and 7-2/MRP RNA (Forster and Altman (1989) Cell 62: 407-409). These data are supportive of the idea that these two RNAs may have evolved from a common progenitor molecule.
Mol Cell Biochem 1994 Jan 12
PMID:Human RNaseP RNA and nucleolar 7-2 RNA share conserved 'To' antigen-binding domains. 751 16

Although the phages P2 and P4 build their capsids from the same precursor, the product of the P2 N gene, the two capsids differ in size: P2 builds a 60 nm, T = 7 capsid from 420 subunits, whereas P4 makes a 45 nm, T = 4 capsid from 240 subunits. This difference leads to substantial changes in shell geometry and subunit interactions. Previous results have demonstrated that the P4 sid gene is responsible for the assembly of P4-sized shells. We have used cryo-electron microscopy and image reconstruction to determine the structure of a putative assembly intermediate of P4 capsids, produced in vivo from cloned genes. We demonstrate that Sid forms a P4-specific scaffold with icosahedral symmetry on the outside of the procapsid-like particles. The Sid molecules (60 or 120 copies) form lofty arches that interact with the gpN hexamers on the icosahedral 2-fold axes, and connect as trimers over the 3-fold axes, forming a continuous dodecahedrally shaped outer cage. The gpN shell inside the Sid cage is approximately 40 nm wide, consistent with the previously suggested maturational expansion. The main difference with respect to the mature P4 capsids is found in the hexamers, which appear strongly elongated and more protruding than in the mature shell. These and previous results are discussed in the light of a model for regulation of capsid size.
J Mol Biol 1995 Aug 04
PMID:The capsid size-determining protein Sid forms an external scaffold on phage P4 procapsids. 764 90

A frozen-hydrated sample embedded in vitreous ice of human alpha 2-macroglobulin transformed by methylamine was imaged by cryoelectron microscopy and reconstructed in three dimensions. In the reconstruction, the cage-like architecture of this protease inhibitor is fully revealed with a clear visualization of two lozenge-shaped lateral walls connected by thin bridges. The shape and dimensions of the internal cavity normally containing the trapped protease(s) is described. The possible locations of the thiol ester sites and inter-subunit connections are also discussed.
J Mol Biol 1993 Jul 20
PMID:Three-dimensional architecture of human alpha 2-macroglobulin transformed with methylamine. 768 27

The extent to which side-chains at the surface of globular proteins adopt well-defined conformations is a matter of some controversy and, in turn, the idea that specific interactions amongst them might make a significant contribution to defining tertiary structures would be generally seen as questionable. In at least some cases, however, there is evidence for organisation of the surface to form discrete, tightly packed clusters. In this paper we examine the role of such clusters in accommodating large, hydrophobic residues on the exterior of protein structures. Taking poplar plastocyanin as a detailed example, we find a variety of ways in which solvent accessibility of such non-polar groups can be limited and we highlight, in particular, a rather simple type of cluster in which a single hydrophobic residue is substantially excluded from solvent by a cage of surrounding, chiefly hydrophilic, side-chains. Comparison with the structures of a number of other proteins which share with plastocyanin the Greek key beta-sandwich topology, but are otherwise unrelated, produces the remarkable finding that analogous clusters are commonly found in the topologically equivalent position. This suggests that these features, which we call small exterior hydrophobic clusters (SEHCs), may have an important structural role and we able that their recurrent position in these proteins is such that they may help to fix the register of non-sequential beta-strands and, perhaps, to specify their association during folding. Similar SEHCs can also be identified in other classes of protein structure and we give a four-helix bundle protein, the rop dimer, as an example. It seems likely that accommodation of large non-polar residues provides a mechanism for introducing a degree of local order in to the surface layers of proteins in solution and it is possible that this behavior could play a role in locking tertiary structures. Thus, while the packing of the hydrophobic core of a globular protein is surely the dominant driving force for folding, it may be that, in some cases at least, interactions among surface residues also play an important role in determining the fine details of the structure.
J Mol Biol 1995 Jun 02
PMID:Conserved structural features on protein surfaces: small exterior hydrophobic clusters. 778 91

The sequence of the gene encoding major outer membrane protein (MOMP) P2 of antigenic variants of non-encapsulated Haemophilus influenzae isolated from persistently infected chronic bronchitis patients was analysed. Antigenic drift was shown to result from single base changes in the P2 gene, all generating amino acid changes in the surface-exposed loops of MOMP P2, predominantly in loop 6. Similar single base changes were observed in H. influenzae persistently present in a subcutaneous cage implanted in rabbits, as well as in a spontaneous H. influenzae mutant that had survived MOMP P2 specific monoclonal-antibody-dependent bactericidal killing in vitro. We hypothesize that accumulation of point mutations under the selection pressure of immunity is a mechanism of antigenic drift of a surface-exposed protein during persistent H. influenzae infection.
Mol Microbiol 1994 Mar
PMID:Antigenic drift of non-encapsulated Haemophilus influenzae major outer membrane protein P2 in patients with chronic bronchitis is caused by point mutations. 802 87


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