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)

Twenty-six mutant forms of simian immunodeficiency virus strain mac239 were constructed with changes in constant region 4 (C4) of env. Twenty-four of these had a single amino acid change, one had changes in two amino acids, and one had a deletion of eight amino acids. The effects of these mutations on viral replication, gp160 processing, and binding of env protein to soluble CD4 receptor were analyzed. The C4 region was relatively sensitive to sequence changes since only 11 of the 26 mutants replicated appreciably. Eight of the 15 mutants that were replication incompetent exhibited grossly defective processing of the gp160 env precursor; these mutations likely resulted in global effects on gp160 structure. Six of the replication incompetent mutants exhibited normal or near normal gp160 processing and binding of env protein to sCD4 and thus were probably blocked at some step subsequent to binding of virus to its CD4 receptor. Only one of the C4 mutations, 441W-->R, resulted in greatly decreased binding to sCD4 while retaining normal processing of gp160. The equivalent residue in HIV-1 has similarly been shown previously to be important for binding of HIV-1 to the CD4 receptor. Since a W-->S mutation at position 441 in C4 of SIVmac239 affected both gp160 processing and sCD4 binding, it is not clear whether the 441 tryptophan is actually important for contacting CD4 or for maintaining an appropriate configuration. mutations within a highly conserved GGDPE sequence in C3 of SIVmac239 specifically affected CD4 binding, which is also similar to previous findings with HIV-1. These results demonstrate similar sequence requirements in SIVmac and HIV-1 env for binding C4, but they raise doubts as to whether C4 sequences are directly involved in the binding.
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PMID:Effects of mutations in constant regions 3 and 4 of envelope of simian immunodeficiency virus. 761 79

We have exploited the sole tryptophan residue (Trp535) in the ribonuclease H (RNase H) domain of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) to study features of the isolated polypeptide (p15 RNase H) by fluorescence spectroscopy. Incubation of purified p15 RNase H with a synthetic RNA/DNA hybrid was accompanied by an alteration in Trp535 fluorescence intensity. This property was used to determine an apparent binding constant (Kapp) of 3.5 x 10(6) M-1 for p15 RNase H complexed with poly(rA)/oligo(dT)12-18 and an occluded site size of 4 nucleotides. A cooperativity coefficient (omega) of 910 was also determined which indicated that nearly three logs of the Kapp were due to cooperativity effects. Recombinant p15 RNase H preparations containing mutations at position 478 (Glu478-->Gln478) or 539 (His539 -->Phe539), which are highly conserved between bacterial and retroviral RNases H, were also analyzed. Under the same conditions, these mutants failed to bind the RNA/DNA hybrid, although they were structurally similar to the wild type polypeptide. Fluorescence spectroscopy thus appears to be an alternative and sensitive means of analyzing functional properties of the purified RNase H domain of HIV-1 RT under a variety of conditions.
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PMID:Fluorimetric analysis of recombinant p15 HIV-1 ribonuclease H. 768 4

Human immunodeficiency virus-1 (HIV-1) protease is catalytically active as a dimer of identical subunits that associate through noncovalent interactions. To investigate the forces stabilizing HIV-1 protease in its active form, we have studied the effects of pH and salts on structure and function of the enzyme. Enzymatic activity was measured by following the hydrolysis of a fluorogenic substrate. Dissociation of the dimer into its subunits was monitored by gel filtration, while conformational changes in the enzyme were probed by measurements of intrinsic tryptophan fluorescence. Mg2+ ions were capable of dissociating the dimeric enzyme with a concomitant red shift and increase in quantum yield of the tryptophan fluorescence, indicating increased accessibility of tryptophan to the aqueous environment. These structural changes also were associated with a loss of catalytic activity which was insensitive to substrate concentration, consistent with noncompetitive inhibition. Both structural and functional changes could be attributed to binding of Mg2+ ions to a site with an apparent dissociation constant of approximately 2 M. In contrast, increasing concentrations of Na ions up to 5 M were without effect. Increasing pH had similar effects on HIV-1 protease as increasing Mg2+ ions concentration, with concomitant dissociation into subunits, increase in quantum yield and red shift in tryptophan fluorescence, and loss in catalytic activity. The apparent pKa for these structural and functional transitions was 6.95 +/- 0.08. This value is consistent with that of an aspartic acid residue with an anomalously high pKa, which has been implicated in the catalytic activity of HIV-1 protease.
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PMID:Effect of pH and nonphysiological salt concentrations on human immunodeficiency virus-1 protease dimerization. 784 Sep 36

T22 ([Tyr5,12,Lys7]-polyphemusin II) was previously synthesized by a solid-phase method and was found to have a strong anti-human immunodeficiency virus (HIV) activity, comparable to that of 3'-azido-2',3'-dideoxy-thymidine (AZT). In the present study, the solution-phase synthesis of T22 was attempted in order to produce this peptide on a large scale. An 18-residue peptide amide corresponding to the entire amino acid sequence of T22 was synthesized by assembling four peptide fragments and two amino acid derivatives, followed by thioanisole-mediated deprotection with 1 M trimethylsilyl trifluoromethanesulfonate (TMSOTf) in trifluoroacetic acid followed by air-oxidation. During this deprotection, a significant by-product derived from the transfer of the p-methoxybenzyl (MBzI) group from the sulfhydryl group of the cysteine residue to the side chain of the tryptophan residue was formed. This side reaction was found to be efficiently suppressed by adopting a two-step deprotection procedure using silver trifluoromethanesulfonate (AgOTf)-TMSOTf or trimethylsilyl bromide (TMSBr)-TMSOTf.
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PMID:Solution-phase synthesis of an anti-human immunodeficiency virus peptide, T22 ([Tyr5,12,Lys7]-polyphemusin II), and the modification of Trp by the p-methoxybenzyl group of Cys during trimethylsilyl trifluoromethanesulfonate deprotection. 789 3

Plasma concentrations of 21 amino acids were determined for 20 control subjects and 20 subjects infected with human immunodeficiency virus type 1 (HIV). Compared with the control subjects, the HIV-infected group had lower cystine, tryptophan, and methionine (decreased 67%, 52%, and 32%, respectively, P < 0.001 for each) and increased taurine (230%, P < 0.001) and lysine concentrations (30%, P < 0.001). Other amino acid concentrations changed modestly. Amounts of cystine, tryptophan, methionine, taurine, and lysine did not differ significantly between subgroups of HIV-infected subjects with > 200 (n = 6) or < 200 (n = 14) CD4+ lymphocytes per microliter, suggesting that the concentrations decrease soon after infection and change little thereafter. Activation of metabolism of cystine to taurine may explain reciprocal changes in these amino acids and known depletion of cystine and glutathione. The selective changes in amino acid profiles observed during HIV infection differ from those recognized for malnutrition or other pathological processes.
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PMID:Changes in plasma amino acid concentrations in response to HIV-1 infection. 790 26

The RNA and DNA complexes of nucleocapsid protein p7.Zn (NCp7.Zn) of the human immunodeficiency virus type 1 (HIV-1) are studied by phosphorescence and optically detected magnetic resonance (ODMR). The single tryptophan, Trp37, which is located on the C-terminal zinc finger domain is used as an intrinsic probe. Reductions in the triplet state zero-field splitting (zfs) D parameter of Trp37 upon complex formation with poly(I) and poly(U) are observed. These results, in conjunction with the phosphorescence red-shifts and triplet state lifetime reductions that are observed, suggest the presence of aromatic stacking interactions between NCp7.Zn and the bases of the RNA polymers. An alteration of the intersystem crossing pattern upon complex formation, in addition to the above mentioned spectroscopic shifts, also is consistent with previously observed tryptophans that undergo stacking interactions with DNA bases [Zang, L.-H., Maki, A.H., Murphy, J.B., & Chase, J.W. (1987) Biophys. J. 52, 867-872. Tsao, D.H.H., Casas-Finet, J.R., Maki, A.H., & Chase, J.W. (1989) Biophys. J. 55, 927-936]. These conclusions support those from a recent ODMR study [Lam, W.-C., Maki, A.H., Casas-Finet, J.R., Erickson, J.W., Sowder, R.C., II, & Henderson, L.E. (1993) FEBS Lett. 328, 45-48] of NCp7.Zn binding to 5-mercurated polyuridylic acid [poly(5-HgU)] in which stacking interactions between the RNA and NCp7.Zn are inferred from the observation of an external heavy atom effect induced on Trp37.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphorescence and optically detected magnetic resonance investigation of the binding of the nucleocapsid protein of the human immunodeficiency virus type 1 and related peptides to RNA. 807 69

The interaction of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 with CD4 CDR3-related peptide derivatives showing anti-HIV-1 activity has been studied. Conformational changes in gp120, which could affect its interaction with CD4 and its shedding from virions, were detected by fluorescence spectrum analysis of tryptophan residues after addition of peptide representative of the CD4 CDR3-related region, but not the CD4 CDR2-related region. Interestingly, the addition of scrambled peptide, S1 (with altered amino acid sequence compared with the native CDR3-related peptide but unaltered overall composition), which we recently showed to have stronger anti-HIV-1 activity than the original CDR3-related peptide, had no effects on the conformational change in gp120 or on its interaction with CD4 and its shedding from HIV-1 virions. However, all of the CDR3-related peptides, including S1, showed blocking effects on the binding of antibodies against gp120 V3 loop and C-terminus regions. Thus, we concluded that there were at least two separable activities of the CDR3-related peptides in anti-HIV-1 activity, i.e. induction of conformational changes in gp120, which could affect its binding to CD4 and to gp41 (as observed in native CDR3-related peptides), and inactivation of V3 loop and C-terminus regions in gp120 (as observed in all of the CDR3-related peptides, including S1).
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PMID:Multiple effects of CD4 CDR3-related peptide derivatives showing anti-HIV-1 activity on HIV-1 gp120 functions. 817 57

The ability to undergo a particular conformational switch on moving from a polar to a less polar environment has been shown to be conserved at the CD4-binding domain of the envelope glycoprotein gp120 from human immunodeficiency virus type 1 despite considerable variability in primary structure and is essential for the process of binding to the T-cell receptor CD4. The elements necessary to the expression of this behavior have been examined in synthetic peptides using circular dichroism and have been found to include a tetrad, LPCR, plus a tryptophan at a position 8 residues C-terminal to it. In the absence of the tryptophan the conformational change from beta-sheet to alpha-helix as medium polarity decreases does not occur abruptly but, rather, in a linear fashion. In the absence of the LPCR tetrad, no transition to alpha-helix occurs even at 100% trifluoroethanol. These two domains interact to control not only the beta-->alpha transition but also both its cooperativity and the critical point on the polar-->apolar gradient at which it occurs. Sequence similarity searches of the protein data banks suggest that an LPCR tetrad, governing the folding behavior of subsequent residues, may occur as a conserved motif in proteins in general. Synthetic peptides with the sequence of non-gp120 proteins that contain the tetrad do in fact display a similar pattern of folding response to decreasing polarity, with a sharp, cooperative transition from beta-sheet to alpha-helix. The LPCR tetrad appears to be a motif that controls secondary structure in a manner supplementary to that predicted by folding algorithms.
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PMID:Primary structure elements responsible for the conformational switch in the envelope glycoprotein gp120 from human immunodeficiency virus type 1: LPCR is a motif governing folding. 834 95

The fourth conserved region (C4) of human immunodeficiency virus type 1 (HIV-1) surface glycoprotein has been shown to participate in CD4 binding and to influence viral tropism (A. Cordonnier, L. Montagnier, and M. Emerman, Nature [London] 340:571-574, 1989). To define the role of the corresponding region of HIV-2, we introduce single amino acid changes into the C4 sequence of HIV-2ROD. The effects of these mutations on glycoprotein function and on virus infectivity have been examined. We have shown that the tryptophan residue at position 428 is necessary primarily for CD4 binding. The isoleucine residue at position 421 is necessary for the establishment of productive infection in the promonocytic cell line U937, while it is dispensable to some extent for infection of primary T lymphocytes or the lymphocytic cell line SUP-T1. This replication defect correlated with the failure of the Ile-421-to-Thr (Ile-421-->Thr) mutant glycoprotein to form syncytia in U937 cells. DNA analysis of revertant viruses revealed that a strong selective pressure was exerted on residue 421 of the surface glycoprotein to allow HIV-2 infection of U937 cells. These results demonstrate that this region of HIV-2 plays an important role in determining fusion efficiency in a cell-dependent manner and consequently can influence viral tropism.
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PMID:Amino acid changes in the fourth conserved region of human immunodeficiency virus type 2 strain HIV-2ROD envelope glycoprotein modulate fusion. 837 58

Changes were introduced into conserved amino acids within the ectodomain of the human immunodeficiency virus type 1 (HIV-1) gp41 transmembrane envelope glycoprotein. The effect of these changes on the structure and function of the HIV-1 envelope glycoproteins was examined. The gp41 glycoprotein contains an amino-terminal fusion peptide (residues 512 to 527) and a disulfide loop near the middle of the extracellular domain (residues 598 to 604). Mutations affecting the hydrophobic sequences between these two regions resulted in two phenotypes. Some changes in amino acids 528 to 562 resulted in a loss of the noncovalent association between gp41 and the gp120 exterior glycoprotein. Amino acid changes in other parts of the gp41 glycoprotein (residues 608 and 628) also resulted in subunit dissociation. Some changes affecting amino acids 568 to 596 resulted in envelope glycoproteins partially or completely defective in mediating membrane fusion. Syncytium formation was more sensitive than virus entry to these changes. Changes in several amino acids from 647 to 675 resulted in higher-than-wild-type syncytium-forming ability. One of these amino acid changes affecting tryptophan 666 resulted in escape from neutralization by an anti-gp41 human monoclonal antibody, 2F5. These results contribute to an understanding of the functional regions of the HIV-1 gp41 ectodomain.
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PMID:Effects of amino acid changes in the extracellular domain of the human immunodeficiency virus type 1 gp41 envelope glycoprotein. 847 72


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