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1.

001-es BibID:BIBFORM040660
Első szerző:Ishima, Rieko
Cím:Folded Monomer of HIV-1 Protease / Ishima R., Ghirlando R., Tözsér J., Gronenborn A. M., Torchia D. A., Louis J. M.
Dátum:2001
ISSN:0021-9258
Megjegyzések:The mature human immunodeficiency virus type 1 protease rapidly folds into an enzymatically active stable dimer, exhibiting an intricate interplay between structure formation and dimerization. We now show by NMR and sedimentation equilibrium studies that a mutant protease containing the R87K substitution (PR(R87K)) within the highly conserved Gly(86)-Arg(87)-Asn(88) sequence forms a monomer with a fold similar to a single subunit of the dimer. However, binding of the inhibitor DMP323 to PR(R87K) produces a stable dimer complex. Based on the crystal structure and our NMR results, we postulate that loss of specific interactions involving the side chain of Arg(87) destabilizes PR(R87K) by perturbing the inner C-terminal beta-sheet (residues 96-99 from each monomer), a region that is sandwiched between the two beta-strands formed by the N-terminal residues (residues 1-4) in the mature protease. We systematically examined the folding, dimerization, and catalytic activities of mutant proteases comprising deletions of either one of the terminal regions (residues 1-4 or 96-99) or both. Although both N- and C-terminal beta-strands were found to contribute to dimer stability, our results indicate that the inner C-terminal strands are absolutely essential for dimer formation. Knowledge of the monomer fold and regions critical for dimerization may aid in the rational design of novel inhibitors of the protease to overcome the problem of drug resistance.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal Of Biological Chemistry. - 276 : 52 (2001), p. 49110-49116. -
További szerzők:Ghirlando, Rodolfo Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Gronenborn, Angela M. Torchia, Dennis A. Louis, John M.
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2.

001-es BibID:BIBFORM040736
Első szerző:Kádas János (molekuláris biológus, biokémikus, kertészmérnök)
Cím:Narrow Substrate Specificity and Sensitivity toward Ligand-binding Site Mutations of Human T-cell Leukemia Virus Type 1 Protease / Kádas J., Weber I. T., Bagossi P., Miklóssy G., Boross P., Oroszlan S., Tözsér J.
Dátum:2004
ISSN:0021-9258
Megjegyzések:Human T-cell leukemia virus type 1 (HTLV-1) is associated with a number of human diseases; therefore, its protease is a potential target for chemotherapy. To compare the specificity of HTLV-1 protease with that of human immunodeficiency virus type 1 (HIV-1) protease, oligopeptides representing naturally occurring cleavage sites in various retroviruses were tested. The number of hydrolyzed peptides as well as the specificity constants suggested a substantially broader specificity of the HIV protease. Amino acid residues of HTLV-1 protease substrate-binding sites were replaced by equivalent ones of HIV-1 protease. Most of the single and multiple mutants had altered specificity and a dramatically reduced folding and catalytic capability, suggesting that mutations are not well tolerated in HTLV-1 protease. The catalytically most efficient mutant was that with the flap residues of HIV-1 protease. The inhibition profile of the mutants was also determined for five inhibitors used in clinical practice and inhibitor analogs of HTLV-1 cleavage sites. Except for indinavir, the HIV-1 protease inhibitors did not inhibit wild type and most of the mutant HTLV-1 proteases. The wild type HTLV-1 protease was inhibited by the reduced peptide bond-containing substrate analogs, whereas the mutants showed various degrees of weakened binding capability. Most interesting, the enzyme with HIV-1-like residues in the flap region was the most sensitive to the HIV-1 protease inhibitors and least sensitive to the HTLV-1 protease inhibitors, indicating that the flap plays an important role in defining the specificity differences of retroviral proteases.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal Of Biological Chemistry. - 279 : 26 (2004), p. 27148-27157. -
További szerzők:Weber, Irene T. Bagossi Péter (1966-2011) (biokémikus, vegyész) Miklóssy Gabriella (1979-) (biológus, vegyész) Boross Péter (1972-) (biokémikus, vegyész) Oroszlan, Stephen Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
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3.

001-es BibID:BIBFORM040666
Első szerző:Louis, John M.
Cím:Stabilization from Autoproteolysis and Kinetic Characterization of the Human T-cell Leukemia Virus Type 1 Proteinase / Louis, J. M., Oroszlan, S., Tözsér, J.
Dátum:1999
ISSN:0021-9258
Megjegyzések:We have developed a system for expression and purification of wild-type human T-cell leukemia virus type 1 (HTLV-1) proteinase to attain sufficient quantities for structural, kinetic, and biophysical investigations. However, similar to the human immunodeficiency virus type 1 (HIV-1) proteinase, HTLV-1 proteinase also undergoes autoproteolysis rapidly upon renaturation to produce two products. The site of this autoproteolytic cleavage was mapped, and a resistant HTLV-1 proteinase construct (L40I) as well as another construct, wherein the two cysteine residues were exchanged to alanines, were expressed and purified. Oligopeptide substrates representing the naturally occurring cleavage sites in HTLV-1 were good substrates of the HTLV-1 proteinase. The kinetic parameters kcat and Km were nearly identical for all the three enzymes. Although three of four peptides representing HTLV-1 proteinase cleavage sites were fairly good substrates of HIV-1 proteinase, only two of nine peptides representing HIV-1 proteinase cleavage sites were hydrolyzed by the HTLV-1 proteinase, suggesting substantial differences in the specificity of the two enzymes. The large difference in the specificity of the two enzymes was also demonstrated by inhibition studies. Of the several inhibitors of HIV-1 or other retroviral proteinases that were tested on HTLV-1 proteinase, only two inhibit the enzyme with a Ki lower than 100 nM.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal Of Biological Chemistry. - 274 : 10 (1999), p. 6660-6666. -
További szerzők:Oroszlan, Stephen Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
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4.

001-es BibID:BIBFORM019934
Első szerző:Mitchell, Michael S.
Cím:Synthesis, processing, and composition of the virion-associated HTLV-1 reverse transcriptase / Michael S. Mitchell, József Tőzsér, Gerald Princler, Patricia A. Lloyd, Ashleigh Auth, David Derse
Dátum:2006
ISSN:0021-9258
Megjegyzések:It is not known whether the low infectivity and low virion-associated polymerase activity of human T-cell lymphotropic virus type-1 (HTLV-1) are due to the quantity or quality of the reverse transcriptase (RT), because the protein has not yet been fully characterized. We have developed anti-RT antibodies and constructed HTLV-1 expression plasmids that express truncated or hemagglutinin-tagged Pol polyproteins to examine the maturation and composition of HTLV-1 RT. We detected virion-associated proteins corresponding to RT-integrase (IN) (pr98) and RT (p62) as well as smaller proteins containing the polymerase (p49) or RNase H domains. We have identified the amino acid sequences in the Pol polyprotein that are cleaved by HTLV-1 protease to yield RT and IN. We have also identified the cleavage sites within RT that give rise to the p49 polymerase fragment. Immunoprecipitation of an epitope-tagged p62 subunit coprecipitated p49, indicating that the HTLV-1 RT complex can exist as a p62/p49 heterodimer analogous to the RT of HIV-1 (p66/p51).
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal of Biological Chemistry. - 281 : 7 (2006), p. 3964-3971. -
További szerzők:Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Princler, Gerald Lloyd, Patricia A. Auth, Ashleigh Derse, David
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Intézményi repozitóriumban (DEA) tárolt változat
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5.

001-es BibID:BIBFORM092752
035-os BibID:(cikkazonosító)100343 (WoS)000672866400317 (Scopus)85102526551
Első szerző:Szabó András (biokémikus)
Cím:Defective binding of SPINK1 variants is an uncommon mechanism for impaired trypsin inhibition in chronic pancreatitis / András Szabó, Vanda Toldi, Lívia Diána Gazda, Alexandra Demcsák, József Tőzsér, Miklós Sahin-Tóth
Dátum:2021
ISSN:0021-9258 1083-351X
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Journal of Biological Chemistry. - 296 (2021), p. 1-13. -
További szerzők:Toldi Vanda (1992-) (molekuláris biológus) Gazda Lívia Diána (1989-) Demcsák Alexandra Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Sahin-Tóth Miklós
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6.

001-es BibID:BIBFORM040699
Első szerző:Tőzsér József (molekuláris biológus, biokémikus, vegyész)
Cím:Comparative studies on the substrate specificity of avian myeloblastosis virus proteinase and lentiviral proteinases / Tözsér J., Bagossi P., Weber I. T., Copeland T. D., Oroszlan S.
Dátum:1996
Megjegyzések:The retroviral proteinase (PR) seems to play crucial roles in the viral life cycle, therefore it is an attractive target for chemotherapy. Previously we studied the specificity of human immunodeficiency virus (HIV) type 1 and type 2 as well as equine infectious anemia virus PRs using oligopeptide substrates. Here a similar approach is used to characterize the specificity of avian myeloblastosis virus (AMV) PR and to compare it with those of the previously characterized lentiviral PRs. All peptides representing naturally occurring Gag and Gag-Pol cleavage sites were substrates of the AMV PR. Only half of these peptides were substrates of HIV-1 PR. The Km values for AMV PR were in a micromolar range previously found for the lentiviral PRs; however, the kcat values were in a 10 30-fold lower range. A series of peptides containing single amino acid substitutions in a sequence representing a naturally occurring HIV cleavage site was used to characterize the seven substrate binding subsites of the AMV PR. The largest differences were found at the P4 and P2 positions of the substrate. Detailed analysis of the results by molecular modeling and comparison with previously reported data revealed the common characteristics of the specificity of the retroviral PRs as well as its strong dependence on the sequence context of the substrate.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:The Journal of biological chemistry. - 271 : 12 (1996), p. 6781-6788. -
További szerzők:Bagossi Péter (1966-2011) (biokémikus, vegyész) Weber, Irene T. Copeland, Terry D. Oroszlan, Stephen
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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7.

001-es BibID:BIBFORM040701
Első szerző:Tőzsér József (molekuláris biológus, biokémikus, vegyész)
Cím:Studies on the Symmetry and Sequence Context Dependence of the HIV-1 Proteinase Specificity / Tözsér J., Bagossi P., Weber I. T., Louis J. M., Copeland T. D., Oroszlan S.
Dátum:1997
ISSN:0021-9258
Megjegyzések:Two major types of cleavage sites with different sequence preferences have been proposed for the human immunodeficiency virus type 1 (HIV-1) proteinase. To understand the nature of these sequence preferences better, single and multiple amino acid substitutions were introduced into a type 1 cleavage site peptide, thus changing it to a naturally occurring type 2 cleavage site sequence. Our results indicated that the previous classification of the retroviral cleavage sites may not be generally valid and that the preference for a residue at a particular position in the substrate depends strongly on the neighboring residues, including both those at the same side and at the opposite side of the peptide backbone of the substrate. Based on these results, pseudosymmetric (palindromic) substrates were designed. The retroviral proteinases are symmetrical dimers of two identical subunits; however, the residues of naturally occurring cleavage sites do not show symmetrical arrangements, and no obvious symmetrical substrate preference has been observed for the specificity of HIV proteinase. To examine the role of the asymmetry created by the peptide bonds on the specificity of the respective primed and nonprimed halves of the binding site, amino acid substitutions were introduced into a palindromic sequence. In general, the results suggested that the asymmetry does not result in substantial differences in specificity of the S3 and S3' subsites, whereas its effect is more pronounced for the S2 and S2' subsites. Although it was possible to design several good palindromic substrates, asymmetrical arrangements may be preferred by the HIV proteinase.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Journal Of Biological Chemistry. - 272 : 27 (1997), p. 16807-16814. -
További szerzők:Bagossi Péter (1966-2011) (biokémikus, vegyész) Weber, Irene T. Louis, John M. Copeland, Terry D. Oroszlan, Stephen
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Intézményi repozitóriumban (DEA) tárolt változat
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