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)

Peptide T, from the human immunodeficiency virus (HIV), whose sequence is Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr, has been shown to inhibit attachment of this virus to T cells and neural cells bearing the CD4 receptor. This peptide shares extensive homology with the 19-26 segment of ribonuclease A (RNase A), whose sequence is Ala-Ala-Ser-Ser-Ser-Asn-Tyr-Cys. Based on comparison of the structures of peptides occurring in proteins of known structure that are homologous to peptide T, viz, RNase A and endothiapepsin and on conformational energy calculations, we predicted that peptide T adopts a structure much like that for residues 19-26 in RNase A. A critical feature is a bend involving residues Thr 4-Asn 7 in peptide T corresponding to Ser 22-Tyr 25 in the RNase A peptide. Our proposed structure for peptide T has recently been confirmed by Cotelle et al. (Biochem. Biophys. Res. Commun. 171, 596-602). We now show directly that the RNase A peptide, with Met replacing Cys 26 to prevent disulfide exchange reactions, strongly induces monocyte-chemotaxis that is blocked by anti-CD4 monoclonal antibody. Both peptide T and RNase A fail to induce chemotaxis, however, in neutrophils which do not express surface CD4 receptors. These results suggest that both peptides interact with the CD4 receptor in inducing monocyte chemotaxis. We have also prepared cyclo-RNase A peptide with Met 26. Using molecular dynamics and conformational energy calculations, we find that the cyclic peptide cannot form a bend structure involving Ser 22-Tyr 25 that is superimposable on the RNase A bend.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Correlation of the conformation of a modified ribonuclease octapeptide, homologous to peptide T, with its ability to induce CD4-dependent monocyte chemotaxis. 144 97

The discovery that the protease from the human immunodeficiency virus (HIV) belongs to the aspartic protease family has generated renewed interest in this class of proteins. In this paper, the interactions of endothiapepsin, an aspartic proteinase from the fungus Endothia parasitica, with the inhibitor pepstatin A have been studied by high-sensitivity calorimetric techniques. These experiments have permitted a complete characterization of the temperature and pH-dependence of the binding energetics. The binding reaction is characterized by negative intrinsic binding enthalpy and negative heat capacity changes. The association constant is maximal at low pH (2 x 10(9) M-1 at pH 3) but decreases upon increasing pH (8.1 x 10(6) M-1 at pH 7). The binding of the inhibitor is coupled to the protonation of one of the aspartic moieties in the Asp dyad of the catalytic site of the protein. This phenomenon is responsible for the decrease in the apparent affinity of the inhibitor for the enzyme upon increasing pH. The experimental results presented here indicate that the binding of the inhibitor is favored both enthalpically and entropically. While the favorable enthalpic contribution is intuitively expected, the favorable entropic contribution is due to the large gain in solvent-related entropy associated with the burial of a large hydrophobic surface, that overcompensates the loss in conformational and translational/rotational degrees of freedom upon complex formation. The characteristics of the molecular recognition process have been evaluated by means of structure-based thermodynamic analysis. Three regions in the protein contribute significantly to the free energy of binding: the residues surrounding the Asp dyad (Asp32 in the N-terminal lobe and Asp215 in the C-terminal domain) and the flap region (Ile73 to Asp77). In addition, the rearrangement of residues that are not in immediate contact with the inhibitor provides close to 40% of the protease contribution to the binding free energy. On the other hand, the two statine residues provide more than half of the inhibitor contributions to the total free energy of binding. It is demonstrated that a previously developed empirical structural parametrization of the thermodynamic parameters that define the Gibbs energy, accurately accounts for the binding energetics and its temperature and pH-dependence.
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PMID:Thermodynamic mapping of the inhibitor site of the aspartic protease endothiapepsin. 756 55

Phosphinate and phosphonate derivatives are potent inhibitors of aspartic proteases (APs). The affinity for the enzyme might be caused by the presence of low barrier hydrogen bonds between the ligand and the catalytic Asp dyad in the cleavage site. We have used density functional theory calculations along with hybrid quantum mechanics/molecular mechanics Car-Parrinello molecular dynamics simulations to investigate the hydrogen-bonding pattern at the binding site of the complexes of human immunodeficiency virus type-1 AP and the eukaryotic endothiapepsin and penicillopepsin. Our calculations are in fair agreement with the NMR data available for endothiapepsin (Coates et al. J. Mol. Biol. 2002, 318, 1405-1415) and show that the most stable active site configuration is the diprotonated, negatively charged form. In the viral complex both protons are located at the catalytic Asp dyad, while in the eukaryotic complexes the proton shared by the closest oxygen atoms is located at the phosphinic/phosphonic group.
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PMID:Binding of phosphinate and phosphonate inhibitors to aspartic proteases: a first-principles study. 1647 95