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)

The trans-activating region (TAR) RNA-Tat protein interaction is important for activation of transciption in the human immunodeficiency virus (HIV). A model complex for this interaction composed of the two base bulge HIV-2 TAR and the amide derivative of arginine was studied by multidimensional heteronuclear NMR. Because of the improved spectral properties of the HIV-2 TAR complex, a larger number of NOEs in the bulge region were observed than in earlier studies of the HIV-1 TAR-argininamide complex. A total of 681 NOE distance restraints were collected and used to determine the solution structure of the HIV-2 TAR-argininamide complex. As observed in the previously proposed model from this lab, the two A-form stems co-axially stack and the critical U23 and the argininamide are located in the major groove. Model calculations including non-experimental restraints indicate that U23 is within hydrogen bonding distance to A27 consistent with the formation of a U x A x U base-triple. Base-triple formation helps open the major groove to increase the accessibility of G26 to hydrogen bond donors from the guanidinium group of argininamide. Argininamide binding is stabilized by stacking of the guanidinium group between the bases of A22 and U23, forming an argininamide sandwich.
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PMID:Solution structure of the HIV-2 TAR-argininamide complex. 912 42

Panels of hybridoma-derived monoclonal antibodies against diverse epitopes are widely used in defining protein surface topography, particularly in the absence of crystal or NMR structural information. Here we show that recombinant monoclonal antibodies from phage display libraries provide a rapid alternative for surface epitope mapping. Diverse epitopes are accessed by presenting antigen to the library in different forms, such as sequential masking of epitopes with existing antibodies or ligands prior to selection and selection on peptides. The approach is illustrated for a recombinant form of the human immunodeficiency virus type 1 (HIV-1) surface glycoprotein gp120 which has been extensively mapped by rodent and human monoclonal antibodies derived by cellular methods. Human recombinant Fab fragments to most of the principal epitopes on gp120 are selected including Fabs to the C1 region, a C1/C5 epitope, a C1/C2 epitope, the V2 loop, the V3 loop and the CD4 binding domain. In addition an epitope linked to residues in the V2 loop and CD4 binding domain is identified. Most of these specificities are associated with epitopes presented poorly on native multimeric envelope, consistent with the notion that these antibodies are associated with immunization by forms of gp120 differing in conformation from that found on whole virus or infected cells.
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PMID:Mapping the protein surface of human immunodeficiency virus type 1 gp120 using human monoclonal antibodies from phage display libraries. 912 46

A single arginine residue within the RNA-binding domain of the human immunodeficiency virus Tat protein makes a critical sequence-specific contact to TAR RNA. Arginine as the free amino acid also binds specifically to TAR and induces a change in RNA conformation similar to that induced by Tat peptides. NMR and biochemical studies have suggested that the arginine-binding site is stabilized by a base triple interaction between a bulged U and an A x U base pair in the adjacent stem. In this study, we have used chemical modification and mutagenesis experiments to examine the relative contributions of the Watson-Crick and Hoogsteen base-pairing partners of the proposed U-A x U base triple. We show that the Hoogsteen interaction is critical for arginine binding whereas the Watson-Crick interaction can be eliminated or replaced by other base-base interactions. The results are consistent with biochemical studies of the Tat-TAR interaction and support the base triple model for the structure of TAR.
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PMID:Dissection of the proposed base triple in human immunodeficiency virus TAR RNA indicates the importance of the Hoogsteen interaction. 913 98

The peptide sequence Gly-Pro-Gly-Arg-Ala-Phe (GPGRAF) is present in many principal neutralizing determinants (PND) of the human immunodeficiency virus type-1 (HIV-1). It has been shown that peptides from the PND sequence contain a significant beta turn in the conserved Gly-Pro-Gly-Arg sequence. In order to find out whether or not the smaller subunits also contain this turn, we have studied the NMR of a hexapeptide [GPGPRAF, peptide (I)], a heptapeptide Gly-Pro-Gly-Arg-Ala-Phe-Cys [GPGRAFC, peptide (II)] and a dodecapeptide [GPGRAFGPGRAF, peptide (III)], retaining the side chain protecting groups. Although the majority of conformations for these peptides are disordered, there is a considerable propensity of structures with beta turn in the GPGR sequence. While peptide (I) and peptide (III) seem to have both type I and type II beta turn conformations, peptide (II) shows a propensity of only type II beta turn. The nascent structures obtained in these peptides may get stabilized as the receptor binding conformation in the presence of the receptors, thus playing a significant role in vaccine development against HIV.
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PMID:NMR study of the peptide present in the principal neutralizing determinant (PND) of HIV-1 envelope glycoprotein gp120. 917 85

The human immunodeficiency virus type 1 Vpu protein enhances virus particle release from infected cells, decreases the tendency of syncytia formation and induces degradation of human CD4 receptor. It is known that the cytoplasmic part of Vpu is responsible for direct interaction to and degradation of CD4. The tertiary fold of the Vpu cytoplasmic domain in aqueous solution was determined employing NMR spectroscopy and molecular-dynamics simulated-annealing protocols. We found a very well defined amphipathic alpha-helix in the membrane proximal part (40-50), a less well defined helix (60-68), and a short alpha-helix at the C-terminus (75-79). We further determined the overall tertiary structure based on long-range nuclear Overhauser enhancement effects. Correlation of results from mutation experiments of Vpu and the structure data is discussed.
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PMID:Secondary structure and tertiary fold of the human immunodeficiency virus protein U (Vpu) cytoplasmic domain in solution. 918 93

Kinetic measurements on a fluorescent peptide analog of the p17/p24 cleavage site of the Gag polyprotein demonstrate the conformational selectivity of human immunodeficiency virus, type 1 protease for the trans conformation of the Tyr-Pro bond. A mean cis/trans ratio of 0. 3, and a cis --> trans isomerization rate constant of 0.022 s-1 are determined at T = 22 degrees C. This rate is in excellent agreement with that predicted by 19F NMR studies of structurally analogous peptides containing a fluorine/hydroxyl substitution on the tyrosyl residue. Addition of recombinant human cyclophilin resulted in a significant enhancement of this rate, and it is proposed that this enzyme, which has been shown to be associated with the Gag protein, functions as an auxiliary enzyme for the protease during cleavage in the virion.
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PMID:Conformational selectivity of HIV-1 protease cleavage of X-Pro peptide bonds and its implications. 918 47

The three-dimensional solution structure of the hybrid duplex r(gaggacug):d(CAGTCCTC) has been determined by two-dimensional NMR, distance geometry (DG), restrained molecular dynamics (rMD) and NOE back-calculation methods. This hybrid, consisting of a purine-rich RNA strand and a pyrimidine-rich DNA strand, is related to the polypurine (+)-strand primer formed after (-)-strand DNA synthesis and RNase H degradation of the viral RNA strand and contains the site of a specific cleavage by reverse transcription (RT) RNase H at the end of the HIV-1 polypurine tract. This polypurine primer is an important intermediate in the formation of virally encoded double-stranded DNA prior to HIV-1 retrovirus integration. The correct processing of this primer is vital in the life cycle of the human immunodeficiency virus type (HIV-1) retrovirus. The structure of the r(gaggacug):d(CAGTCCTC) hybrid, as determined in solution by NMR, is intermediate between canonical A-type and B-type double helices, and has mixed structural characteristics. It is quantitatively different from the previously determined solution structures of other RNA-DNA hybrids, particularly in the width and shape of the major groove, which is wider than the major groove of other hybrids and is close to the dimension of the major groove of B-type DNA duplexes. The structure of this hybrid duplex contains a prominent bend in the double helix with a magnitude and direction similar to the bend in Okazaki fragments. The structural features of the present duplex may explain the unique interactions of this sequence with HIV-1 RT during both (-)-strand and (+)-strand DNA synthesis.
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PMID:Solution structure of r(gaggacug):d(CAGTCCTC) hybrid: implications for the initiation of HIV-1 (+)-strand synthesis. 919 Oct 67

Two-dimensional NMR, circular dichroism (CD) experiments and molecular modeling were performed to study the secondary structure of a 44-mer peptide fragment derived from the C4 region of gp120 of human immunodeficiency virus in aqueous solution. It was found a nascent helical structure exists following a type I turn near the N-terminus of the peptide. The proline residue in the turn appears to serve as a helix initiator. The helical structure was in fast dynamic equilibrium with beta- or random coil form on the NMR scale. A reverse turn was identified at a section containing two consecutive proline residues. A nascent helical structure has been detected for the region near the C-terminus of the 44-mer peptide. Higher helical content for the peptide is also indicated by CD studies on TFE titration. Thus it is proposed that, in more apolar medium, the Pro-Pro turn and the segment amino-terminal to it, spanning about 20 amino acids, may be converted into helix structure. Moreover, the region near the C-terminus of the peptide may also be induced into helix, so that a helix-turn-helix structure may be formed in the C4 domain of gp120. A helical wheel representation of this stretch shows amphipathicity of the helix. The biological implication of the conformational adaptibility of the peptide was discussed.
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PMID:NMR and circular dichroism studies on the conformation of a 44-mer peptide from a CD4-binding domain of human immunodeficiency virus envelope glycoprotein. 921 Dec 25

The principal neutralizing determinant (PND) of human immunodeficiency virus type 1 (HIV-1) is located in the third hypervariable region (V3) of the virus envelope glycoprotein gp120. The conformation of a V3 peptide of HIV-1IIIB bound to the Fab fragment of an anti-gp120 HIV neutralizing antibody, 0.5beta, was studied by 1H NMR spectroscopy. This 18-residue peptide represents the epitope recognized by 0.5beta and encompasses most of the PND. The slow off-rate of the peptide prevents the observation of peptide/Fab interactions as well as intramolecular interactions within the bound peptide by transferred nuclear Overhauser enhancement (TRNOE). To detect and assign interactions within the bound peptide in the 52 kDa complex, NOESY difference spectra were measured using three strategies: (a) deuteration of peptide residues, (b) Arg two head right arrow Lys replacements, and (c) truncation of the peptide antigen. Each difference spectrum was calculated between NOESY spectra measured for two Fab complexes in which the bound peptides differed in their deuteration or in their sequence. The difference spectra revealed numerous interactions between the N-terminus of the epitope (Arg-4, Lys-5, Ser-6, Ile-7, and Ile-9) and its C-terminus (Phe-17, Val-18, Thr-19, and Ile-20). The assigned NOE interactions within the bound peptide were translated into distance restraints that were used to calculate the conformation of the bound peptide by the hybrid distance geometry/simulated annealing method. A total of 39 long-range (residues i - j >> 4), 14 short-range, and 69 intraresidue NOE interactions within the bound peptide have been assigned. Twelve structures without NOE constraint violations were obtained, having a 1.6 A rms deviation for the backbone atoms. The peptide forms a 10-residue loop, while the two segments flanking this loop, KSI and VTI, interact extensively with each other and possibly form antiparallel beta-strands. This loop conformation could be observed due to the unusual large size (17 residues) of the antigenic determinant recognized by 0.5beta.
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PMID:Conformation of the principal neutralizing determinant of human immunodeficiency virus type 1 in complex with an anti-gp120 virus neutralizing antibody studied by two-dimensional nuclear magnetic resonance difference spectroscopy. 921 8

Expression of the structural proteins of human immunodeficiency virus type 1 (HIV-1) requires the direct interaction of multiple copies of the viral protein Rev with its target RNA, the Rev response element (RRE). RRE is a complex 351-nt RNA that is highly structured and located within the viral env gene. During initial Rev-RRE recognition, Rev binds with high affinity to a bubble structure located within the RRE RNA stem-loop II. We have used a site-specific photocrosslinking method based on 6-thioguanosine (6-thioG) photochemistry to probe the conformation of the high-affinity binding site of RRE RNA and its interactions with Rev protein under physiological conditions. A minimal duplex RNA containing the bubble region of RRE and 12 flanking base pairs was synthesized chemically. Two different RRE constructs with a single photoactive nucleoside (6-thio-dG or 6-thioG) at position 47 or 48 were synthesized. Upon UV irradiation, 6-thioG at both positions formed interstrand covalent crosslinks in RRE RNA. Mapping of crosslink sites by RNA sequencing revealed that 6-thioG at position 47 or 48 crosslinked to A73. In the presence of Rev, both RNA-RNA and RNA-protein crosslinks were observed, however, the RNA-RNA crosslink site was unchanged. Our results provide direct evidence that, during RNA-protein recognition, Rev is in close proximity to O6 of G47 and G48 in the major groove of RRE RNA. Our results also show that the bubble region of RRE RNA has a biologically relevant structure where G47 and G48 are in close proximity to A73 and this RNA structure is not changed significantly upon Rev binding. We propose that Rev protein recognizes and binds to specific structural elements of RRE RNA containing non-Watson-Crick base pairs and such structures could be a determinant for recognition by other RNA-binding proteins. Our site-specific crosslinking methods provide a general approach to capture dynamic states of biologically relevant RNA structures that are otherwise missed by NMR and X-ray crystallographic studies.
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PMID:Dynamics of RNA-protein interactions in the HIV-1 Rev-RRE complex visualized by 6-thioguanosine-mediated photocrosslinking. 925 44


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