Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NMR and CD studies were carried out on a peptide representing the hydrophobic N-terminal domain of envelope glycoprotein of human immunodeficiency virus type-1 in solutions of varying polarity. It was found that in aquaeous solution the amide proton of glycine in the FLG motif resonated at a considerably high field and its chemical shift, within the limit of experimental precision, had a temperature coefficient of zero in the range studied. The upfield shift of NH of the glycine could be largely attributed to the ring-current effect of phenylalanine in the FLG motif that participated in a type-1 beta turn with a short Cbeta(i)-NH(i+2) distance. The slower proton-deuterion exchange for the glycine amide proton relative to that of other glycines was consistent with a folded structure for the motif in aquaeous solution. Results of the molecular simulation showed that this proton was shielded from the solvent by non-polar side chains of the amino acid residues surrounding the turn stabilized by hydrophobic interactions, thus explaining the zero temperature coefficient of the proton chemical shift. The structural stabilizing effect of the hydrophobic interaction was supported by the behavior of the proton in less polar Me2SO solution, in which the anomaly in the chemical shift and its temperature coefficient was less prominent. Detailed secondary-structure analysis suggested that the beta turn of the FLG motif may act as an initiation core for helix formation, probably because the turn readily transforms into helical form.
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PMID:The FLG motif in the N-terminal region of glucoprotein 41 of human immunodeficiency virus type 1 adopts a type-I beta turn in aqueous solution and serves as the initiation site for helix formation. 928 13

The gp41 protein of the human (HIV) and simian (SIV) immunodeficiency viruses is part of the envelope glycoprotein complex gp41/gp120 which plays an essential role in viral infection. We present a multidimensional NMR study on the trimeric 44 kDa soluble ectodomain of SIV gp41 (e-gp41), comprising residues 27 to 149. Despite the large molecular weight and very limited spectral dispersion, complete backbone 1H, 13C, 13CO and 15N assignments have been made using a combination of triple resonance experiments on uniformly 13C/15N and 2H/13C/15N-labeled samples. The secondary structure of SIV e-gp41, derived on the basis of 13C chemical shifts, NH exchange rates, medium range nuclear Overhauser enhancements (NOE), and 3JHNalpha coupling constants, consists of a 49 residue helix at the N terminus (residues 29 to 77) and a 40 residue helix at the C terminus (residues 108 to 147), connected by a 30 residue loop which does not display any of the characteristics of regular secondary structure. The cross-peak intensities of the loop region in scalar correlation experiments suggests that it is more mobile than the core helical regions. The presence, however, of numerous long range NOEs, both intra and inter-subunit, within the loop indicates that it adopts a well-defined structure in which the loops from the three subunits interact with each other. Based on a number of long range intra and inter-subunit NOEs, a topological model is presented for the symmetric SIV e-gp41 trimer in which the N-terminal helices are packed within the protein interior in a parallel trimeric coiled-coil arrangement, while the C-terminal helices are located on the protein exterior, oriented antiparallel to the N-terminal helices.
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PMID:Determination of the secondary structure and global topology of the 44 kDa ectodomain of gp41 of the simian immunodeficiency virus by multidimensional nuclear magnetic resonance spectroscopy. 929 29

The product of the nusB gene of Escherichia coli modulates the efficiency of transcription termination at nut (N utilization) sites of various bacterial and bacteriophage lambda genes. Similar control mechanisms operate in eukaryotic viruses (e.g. human immunodeficiency virus). A recombinant strain of E. coli producing relatively large amounts of NusB protein (about 10% of cell protein) was constructed. The protein could be purified with high yield by anion-exchange chromatography followed by gel-permeation chromatography. The protein is a monomer of 15.6 kDa as shown by analytical ultracentrifugation. Structural studies were performed using protein samples labelled with 15N, 13C and 2H in various combinations. Heteronuclear three-dimensional triple-resonance NMR experiments combined with a semi-automatic assignment procedure yielded the sequential assignment of the 1H, 13C and 15N backbone resonances. Based on experimentally derived scalar couplings, chemical-shift values, amide-exchange data, and a semiquantitative interpretation of NOE data, the secondary structure of NusB has classified as alpha helical, comprising seven alpha helices.
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PMID:Studies on the NusB protein of Escherichia coli--expression and determination of secondary-structure elements by multinuclear NMR spectroscopy. 934 86

Specific interactions between the 72-amino acid nucleocapsid protein NCp7 of the human immunodeficiency virus, type 1 and the genomic RNA are essential for virus replication. Studies on the mechanism of action of NCp7 require a direct visualization of its complexes with nucleic acids and the determination of binding affinities. To facilitate these investigations, fluorescent NCp7 derivatives were developed by introduction in the NCp7 sequence of a non-natural amino acid, (S)-beta-(9-acridinyl)alanine (Aca) obtained by a chiral synthetic method. Three fluorescent NCp7 derivatives were obtained by introducing this amino acid at different positions. As shown by NMR, the three-dimensional structure of NCp7 is not altered by introduction of Aca. The fluorescent peptides were found to be as potent as their precursors in interacting with nucleic acids and in promoting HIV-1 genomic RNA dimerization. Moreover, because of their fluorescent properties, these NCp7s can be used at submicromolar concentrations to directly visualize and quantify protein-nucleic acid interactions in solution or after gel electrophoresis. This could facilitate the development of new antiviral agents aimed at inhibiting the functions of NCp7 and studies on the intracellular traffic of NCp7 within the preintegration complex.
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PMID:Synthesis and biological activities of fluorescent acridine-containing HIV-1 nucleocapsid proteins for investigation of nucleic acid-NCp7 interactions. 935 65

Human immunodeficiency virus Nef protein accelerates virulent progression of AIDS by its interaction with specific cellular proteins involved in cellular activation and signal transduction. Here we report the purification and crystallization of the conserved core of HIV-1LAI Nef protein in the unliganded form and in complex with the wild-type SH3 domain of the P59fyn protein-tyrosine kinase. One-dimensional NMR experiments show that full-length protein and truncated fragment corresponding to the product of HIV-1 protease cleavage have a well-folded compact tertiary structure. The ligand-free HIV-1 Nefcore protein forms cubic crystals belonging to space group P23 with unit cell dimensions of a = b = c = 86.4 A. The Nef-Fyn SH3 cocrystals belong to the space group P6(1)22 or its enantiomorph, P6(5)22, with unit cell dimensions of a = b = 108.2 A and c = 223.7 A. Both crystal forms diffract to a resolution limit of 3.0 A resolution using synchrotron radiation, and are thus suitable for X-ray structure determination.
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PMID:HIV-1 Nef protein: purification, crystallizations, and preliminary X-ray diffraction studies. 941 24

The solution conformations of the all L-alpha-peptide 1 and the corresponding retro-all D-alpha-peptide 2, two 20-metric peptides which generate antibodies that cross-react with the gp 120 envelop protein of human immunodeficiency virus-1 (HIV-1), have been investigated by high-field 1H NMR spectroscopy. Complete sequential and inter-residue interaction assignments were made from the 2D NMR spectra acquired at 500 MHz and 600 MHz in 40% deuterotrifluoroethanol (d3-TFE)/H2O at pH 2.3, and in 300 mM sodium dodecyl sulphate (SDS) in 100% D2O or 90% H2O/10% D2O at pH 2.6. Based on analysis of the nuclear Overhauser effect (NOE) and amide exchange data, peptide 1 and its retro-inverso isomer 2 in the polar solvent environment of 40% d3-TFE/H2O at pH 2.3 show very similar topological features. However, in the relatively non-polar 300 mM SDS micellar environment, peptides 1 and 2 exhibit differences in their solution structures in terms of the amide backbone and side-chain orientations. In particular, under the SDS micellar condition, peptide 1 maintains much of the secondary structure observed for this 20-mer peptide in 40% d3-TFE/H2O, pH 2.3, whereas peptide 2 adopts a more extended structure. These NMR results provide the first confirmation that the secondary structure of the all L-a-peptide 1 is maintained in both polar and non-polar environments, whereas the secondary structure and topology of the notionally equivalent retro-inverso isomer depends more on the solvent conditions. These results with the all L-a-peptide 1 and its retro-inverso isomer 2 provide important insight into the conformational influences of the C- and N-end group with L-alpha- and retro-D-alpha-isomer pairs in non-polar environments, and thus have general relevance to the design of bioactive retro-inverso peptidomimetic analogues related to immunogenic or hormonal peptides.
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PMID:Comparison of the solution conformations of a human immunodeficiency virus peptidomimetic and its retro-inverso isomer using 1H NMR spectroscopy. 944 43

Lentiviral transactivator (Tat) proteins are essential for viral replication. Tat proteins of human immunodeficiency virus type 1 and bovine immunodeficiency virus form complexes with their respective RNA targets (Tat responsive element, TAR), and specific binding of the equine anemia virus (EIAV) Tat protein to a target TAR RNA is suggested by mutational analysis of the TAR RNA. Structural data on equine infectious anemia virus Tat protein reveal a helix-loop-helix-turn-helix limit structure very similar to homeobox domains that are known to bind specifically to DNA. Here we report results of gel-shift and footprinting analysis as well as fluorescence and nuclear magnetic resonance spectroscopy experiments that clearly show that EIAV Tat protein binds to DNA specifically at the long terminal repeat Pu.1 (GTTCCTGTTTT) and AP-1 (TGACGCG) sites, and thus suggest a common mechanism for the action of some of the known lentiviral Tat proteins via the AP-1 initiator site. Complex formation with DNA induces specific shifts of the proton NMR resonances originating from amino acids in the core and basic domains of the protein.
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PMID:Equine infectious anemia virus transactivator is a homeodomain-type protein. 954 68

The main transcriptional regulator of the human immunodeficiency virus, the Tat protein, recognizes and binds to a small structured RNA element at the 5' end of every viral mRNA, termed TAR. On the basis of published structural data of the molecular interactions between TAR and Tat-related peptides, we defined requirements for potential low-molecular weight inhibitors of TAR recognition by the Tat protein. In accordance with the resulting concept, a series of compounds was synthesized. In vitro evaluation of their potential to directly interfere with Tat-TAR interaction was used to define a new chemical class of potent Tat antagonistic substances. The most active compound competed with Tat-TAR complexation with a competition dose CD50 of 22 nM in vitro and blocked HIV expression in a cellular Tat transactivation system with an IC50 of 1.2 microM. The close relation between structural features of the interaction between TAR and a new type of inhibitory agent, "In-PRiNts" (for inhibitor of protein-ribonucleotide sequences), such as CGP 40336A and those of the Tat-TAR complex was confirmed by RNase A footprinting and by two-dimensional NMR. Structural implications for the complex between this class of compounds and TAR RNA will be presented.
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PMID:A new class of HIV-1 Tat antagonist acting through Tat-TAR inhibition. 954 39

Here, we describe an application of the backbone cyclic (BC) proteinomimetic approach to the design and the synthesis of a BC peptide which functionally mimics the nuclear localization signal (NLS) region of the human immunodeficiency virus type 1 matrix protein (HIV-1 MA). On the basis of the NMR structure of HIV-1 MA, a library of BC peptides was designed and screened for the ability to inhibit nuclear import of NLS-BSA in digitonin-permeabilized HeLa and Colo-205 cultured cells. The screening yielded a lead compound (IC50 = 3 microM) which was used for the design of a second library. This library led to the discovery of a highly potent BC peptide, designated BCvir, with an IC50 value of 35 nM. This inhibitory potency is compared to a value of 12 microM exhibited by the linear parent HIV-1 MA NLS peptide. BCvir also reduced HIV-1 production by 75% in infected nondividing cultured human T-cells and was relatively resistant to tryptic digestion. These properties make BCvir a potential candidate for the development of a novel class of antiviral drugs which will be based on blocking nuclear import of viral genomes.
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PMID:Backbone cyclic peptide, which mimics the nuclear localization signal of human immunodeficiency virus type 1 matrix protein, inhibits nuclear import and virus production in nondividing cells. 954 47

Retroviral protease (PR) from the human immunodeficiency virus type 1 (HIV-1) was identified over a decade ago as a potential target for structure-based drug design. This effort was very successful. Four drugs are already approved, and others are undergoing clinical trials. The techniques utilized in this remarkable example of structure-assisted drug design included crystallography, NMR, computational studies, and advanced chemical synthesis. The development of these drugs is discussed in detail. Other approaches to designing HIV-1 PR inhibitors, based on the concepts of symmetry and on the replacement of a water molecule that had been found tetrahedrally coordinated between the enzyme and the inhibitors, are also discussed. The emergence of drug-induced mutations of HIV-1 PR leads to rapid loss of potency of the existing drugs and to the need to continue the development process. The structural basis of drug resistance and the ways of overcoming this phenomenon are mentioned.
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PMID:Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. 964 69


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