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)

We describe the isolation and characterization of cDNA clones encoding human leukosialin, a major sialoglycoprotein of human leukocytes. Leukosialin is very closely related or identical to the sialophorin molecule, which is involved in T-cell proliferation and whose expression is altered in Wiskott-Aldrich syndrome (WAS), an X chromosome-linked immunodeficiency disease. Using a rabbit anti-serum to leukosialin, a cDNA clone was isolated from a lambda gt11 cDNA library constructed from human peripheral blood cells. This lambda gt11 clone was used to isolate longer cDNA clones that correspond to the entire coding sequence of leukosialin. DNA sequence analysis reveals three domains in the predicted mature protein. The extracellular domain is enriched for Ser, Thr, and Pro and contains four contiguous 18-amino acid repeats. The transmembrane and intracellular domains of the human leukosialin molecule are highly homologous to the rat W3/13 molecule. RNA gel blot analysis reveals two polyadenylylated species of 2.3 and 8 kilobases. Southern blot analysis suggests that human leukosialin is a single-copy gene. Analysis of monochromosomal cell hybrids indicates that the leukosialin gene is not X chromosome linked and in situ hybridization shows leukosialin is located on chromosome 16. These findings demonstrate that the primary mutation in WAS is not a defect in the structural gene for leukosialin.
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PMID:Characterization of cDNAs encoding human leukosialin and localization of the leukosialin gene to chromosome 16. 252 52

Retroviral gag, pol and env gene products are translated as precursor polyproteins, which are cleaved by virus-encoded proteases to produce the mature proteins found in virions. On the basis of the conserved Asp-Thr/Ser-Gly sequence at the putative protease active sites, and other biochemical evidence, retroviral proteases have been predicted to be in the family of pepsin-like aspartic proteases. It has been suggested that aspartic proteases evolved from a smaller, dimeric ancestral protein, and a recent model of the human immunodeficiency virus (HIV) protease postulated that a symmetric dimer of this enzyme is equivalent to a pepsin-like aspartic protease. We have now determined the crystal structure of Rous sarcoma virus (RSV) protease at 3-A resolution and find it is dimeric and has a structure similar to aspartic proteases. This structure should provide a useful basis for the modelling of the structures of other retroviral proteases, such as that of HIV, and also for the rational design of protease inhibitors as potential antiviral drugs.
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PMID:Crystal structure of a retroviral protease proves relationship to aspartic protease family. 253 2

Conformational analysis, based on ECEPP (Empirical Conformational Energy Program for Peptides) using the chain build-up procedure, was applied to determine the low-energy conformations for a series of tetrapeptides. The tetrapeptides are components of larger peptides which have been found to bind to the CD4 receptor of monocytes. Several previous studies have implicated the tetrapeptide units investigated here as being critical to the biological activities of the full peptides. Five such tetrapeptides were studied: Ser-Ser-Asn-Tyr (from ribonuclease A), Thr-Thr-Asn-Tyr (from peptide T, known to block human immunodeficiency virus from attaching to CD4+ T cells), Thr-Ile-Asn-Tyr (from polio virus coat protein, which is less active than the other peptides in binding to CD4 receptors), Ser-Ser-Ala-Tyr (from the gp 120 coat protein of human immunodeficiency virus, a variant of the peptide T sequence, active in blocking viral attachment to CD4+ cells), and the tetrapeptide from an active synthetic pentapeptide, Asn-Thr-Lys-Tyr (from Asn-Thr-Lys-Tyr-Thr). Using a 7 kcal/mol cutoff, the low-energy conformations for each peptide were computed. Approximately 20,000 conformations were computed for each tetrapeptide. Residue probability profiles were determined for each tetrapeptide. All tetrapeptides except for the polio sequence showed flexibility in the sense that many low-energy conformations were possible. In previous studies, it was postulated that the critical tetrapeptide units would adopt conformations similar to the one observed in a segment of ribonuclease A, residues 22-25, a beta-bend, which is part of an octapeptide segment (residues 19-26) that is homologous to the sequence of peptide T.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Correlation of beta-bend conformations of tetrapeptides with their activities in CD4-receptor binding assays. 259 73

The envelope glycoproteins of the human immunodeficiency virus (HIV) type 1 are synthesized as a precursor molecule, gp160, which is cleaved to generate the two mature envelope glycoproteins, gp120 and gp41. The cleavage reaction, which is mediated by a host protease, occurs at a sequence highly conserved in retroviral envelope glycoprotein precursors. We have investigated the sequence requirements for this cleavage reaction by introducing four single-amino-acid changes into the glutamic acid-lysine-arginine sequence immediately amino terminal to the site of cleavage. We have also examined the effects of these mutations on the syncytium formation induced by HIV envelope glycoproteins. Our results indicate that a glutamic acid to glycine change at gp120 amino acid 516, a lysine to isoleucine change at amino acid 517, and an arginine to lysine change at amino acid 518 affect neither gp160 cleavage nor syncytium formation. The results obtained with the arginine to lysine change at amino acid 518 differ significantly from the results obtained with the same mutation at the envelope precursor cleavage site of a murine leukemia virus (E. O. Freed, and R. Risser, J. Virol. 61:2852-2856, 1987). An arginine to threonine mutation at gp120 amino acid 518, the terminal residue of gp120, abolishes both gp160 cleavage and syncytium formation. These findings demonstrate that despite its highly conserved nature, the basic pair of amino acids at the site of gp160 cleavage is not absolutely required for proper envelope glycoprotein processing. This report also supports the idea that cleavage of gp160 is required for activation of the HIV envelope fusion function.
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PMID:Mutational analysis of the cleavage sequence of the human immunodeficiency virus type 1 envelope glycoprotein precursor gp160. 267

Knowledge of the tertiary structure of the proteinase from human immunodeficiency virus HIV-1 is important to the design of inhibitors that might possess antiviral activity and thus be useful in the treatment of AIDS. The conserved Asp-Thr/Ser-Gly sequence in retroviral proteinases suggests that they exist as dimers similar to the ancestor proposed for the pepsins. Although this has been confirmed by X-ray analyses of Rous sarcoma virus and HIV-1 proteinases, these structures have overall folds that are similar to each other only where they are also similar to the pepsins. We now report a further X-ray analysis of a recombinant HIV-1 proteinase at 2.7 A resolution. The polypeptide chain adopts a fold in which the N- and C-terminal strands are organized together in a four-stranded beta-sheet. A helix precedes the single C-terminal strand, as in the Rous sarcoma virus proteinase and also in a synthetic HIV-1 proteinase, in which the cysteines have been replaced by alpha-aminobuytric acid. The structure reported here provides an explanation for the amino acid invariance amongst retroviral proteinases, but differs from that reported earlier in some residues that are candidates for substrate interactions at P3, and in the mode of intramolecular cleavage during processing of the polyprotein.
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PMID:X-ray analysis of HIV-1 proteinase at 2.7 A resolution confirms structural homology among retroviral enzymes. 268 66

The structure of a complex between a peptide inhibitor with the sequence N-acetyl-Thr-Ile-Nle-psi[CH2-NH]-Nle-Gln-Arg.amide (Nle, norleucine) with chemically synthesized HIV-1 (human immunodeficiency virus 1) protease was determined at 2.3 A resolution (R factor of 0.176). Despite the symmetric nature of the unliganded enzyme, the asymmetric inhibitor lies in a single orientation and makes extensive interactions at the interface between the two subunits of the homodimeric protein. Compared with the unliganded enzyme, the protein molecule underwent substantial changes, particularly in an extended region corresponding to the "flaps" (residues 35 to 57 in each chain), where backbone movements as large as 7 A are observed.
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PMID:Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution. 268 29

Sialophorin (CD43) of leukocytes and platelets is a surface sialoglycoprotein that is phenotypically defective on lymphocytes of patients with the X chromosome-linked immunodeficiency Wiskott-Aldrich syndrome. Previous studies with monoclonal antibodies indicate that sialophorin is a component of a T-lymphocyte activation pathway. Here we describe the cDNA cloning and derived amino acid sequence of human sialophorin. The sequence predicts an integral membrane polypeptide with an N-terminal hydrophobic signal region followed by a mucin-like 235-residue extracellular region with a uniform distribution of 46 serine, 47 threonine, and 24 proline residues. This is followed by a 23-residue transmembrane region and a 123-residue C-terminal intracellular region. These latter regions have been highly conserved during evolution; the intracellular region contains a number of potential phosphorylation sites that might mediate transduction of activation signals. The chromosomal location of the sialophorin gene was determined and the implications of this assignment for the pathogenesis of the Wiskott-Aldrich syndrome are discussed.
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PMID:Molecular characterization of sialophorin (CD43), the lymphocyte surface sialoglycoprotein defective in Wiskott-Aldrich syndrome. 278 59

The octapeptide Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr (peptide T) and two structural analogs are potent agonists of human monocyte chemotaxis, evincing identical rank potency orders as was previously shown for their inhibition of human immunodeficiency virus (HIV) envelope binding and T cell infectivity. Chemotactic activity could be inhibited by anti-CD4 monoclonal antibodies (Mabs), but not other mononuclear cell Mabs. The core peptide required for chemotactic activity is a pentapeptide related to the sequence Thr-Thr-Asn-Tyr-Thr. Homologous pentapeptides, identified by computer search, were detected in several other non-HIV-related viruses as well as the neuropeptide vasoactive intestinal polypeptide (VIP). The CD4 molecule, therefore, appears to be a recognition molecule for a small signal peptide ligand whose active sequence is a homolog of peptide T and which may be the neuropeptide VIP.
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PMID:CD4 receptor binding peptides that block HIV infectivity cause human monocyte chemotaxis. Relationship to vasoactive intestinal polypeptide. 302 40

In many retroviruses the 5' end of the pol gene codes for a protease vital for the processing of the gag polyprotein into the separate core proteins. In some viruses this protease is encoded at the 3' end of the gag gene, or between the gag and pol genes in a different reading frame to either. A sequence, Asp-Thr-Gly, which is conserved in retroviral proteases is also conserved in the active sites of aspartic proteases, an observation which has led to the suggestion that the retroviral proteases could belong to this family. We have examined the sequences of the aspartic and retroviral protease families, using pattern-recognition, structure prediction and molecular modelling techniques, and conclude that the viral protease sequences probably correspond to a single domain of an aspartic protease and may function in a dimeric form. We have constructed a model of the pol-protease of human immunodeficiency virus 1 (HIV-1) to test this hypothesis.
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PMID:A structural model for the retroviral proteases. 330 11

A recently proposed octapeptide, [D-Ala]peptide T amide (D-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2), has been shown to bind to the CD4 receptor on human T-cell lymphocytes and block human immunodeficiency viral infectivity. This peptide may not only be itself a promising therapeutic for the disease of AIDS (acquired immune deficiency syndrome), but might open a new avenue of research towards more efficacious drugs. Accordingly, a counter-current chromatography system is here presented, utilizing the Ito flow-through coil planet centrifuge (solvent system, 1% trifluoroacetic acid-n-butanol (1:1), upper phase mobile) which allows facile preparative purification of [D-Ala]peptide T amide. The method may be applicable to purifying analogues of [D-Ala]peptide T amide as they are developed.
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PMID:Counter-current chromatographic purification of [D-Ala]peptide T amide. 344 32


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