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1.

001-es BibID:BIBFORM040648
Első szerző:Boross Péter (biokémikus, vegyész)
Cím:Effect of substrate residues on the P2' preference of retroviral proteinases / Boross Peter, Bagossi Peter, Copeland Terry D., Oroszlan Stephen, Louis John M., Tozser Jozsef
Dátum:1999
ISSN:0014-2956
Megjegyzések:The substrate sequence requirements for preference toward P2' Glu residue by human immunodeficiency virus type 1 (HIV-1) proteinase were studied in both the matrix protein/ capsid protein (MA/CA) and CA/p2 cleavage site sequence contexts. These sequences represent typical type 1 (-aromatic*Pro-) and type 2 (-hydrophobic* hydrophobic-) cleavage site sequences, respectively. While in the type 1 sequence context, the preference for P2' Glu over Ile or Gln was found to be strongly dependent on the ionic strength and the residues being outside the P2-P2' region of the substrate, it remained preferable in the type 2 substrates when typical type 1 substrate sequence residues were substituted into the outside regions. The pH profile of the specificity constants suggested a lower pH optimum for substrates having P2' Glu in contrast to those having uncharged residues, in both sequence contexts. The very low frequency of P2' Glu in naturally occurring retroviral cleavage sites of various retroviruses including equine infectious anemia virus (EIAV) and murine leukemia virus (MuLV) suggests that such a residue may not have a general regulatory role in the retroviral life cycle. In fact, unlike HIV-1 and HIV-2, EIAV and MuLV proteinases do not favor P2' Glu in either the MA/CA or CA/p2 sequence contexts.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:European Journal Of Biochemistry. - 264 : 3 (1999), p. 921-929. -
További szerzők:Bagossi Péter (1966-2011) (biokémikus, vegyész) Copeland, Terry D. Oroszlan, Stephen Louis, John M. Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
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2.

001-es BibID:BIBFORM040655
Első szerző:Fehér Anita
Cím:Effect of sequence polymorphism and drug resistance on two HIV-1 Gag processing sites / Fehér Anita, Weber Irene T., Bagossi Péter, Boross Péter, Mahalingam Bhuvaneshwari, Louis John M., Copeland Terry D., Torshin Ivan Y., Harrison Robert W., Tözsér József
Dátum:2002
ISSN:0014-2956
Megjegyzések:The HIV-1 proteinase (PR) has proved to be a good target for antiretroviral therapy of AIDS, and various PR inhibitors are now in clinical use. However, there is a rapid selection of viral variants bearing mutations in the proteinase that are resistant to clinical inhibitors. Drug resistance also involves mutations of the nucleocapsid/p1 and p1/p6 cleavage sites of Gag, both in vitro and in vivo. Cleavages at these sites have been shown to be rate limiting steps for polyprotein processing and viral maturation. Furthermore, these sites show significant sequence polymorphism, which also may have an impact on virion infectivity. We have studied the hydrolysis of oligopeptides representing these cleavage sites with representative mutations found as natural variations or that arise as resistant mutations. Wild-type and five drug resistant PRs with mutations within or outside the substrate binding site were tested. While the natural variations showed either increased or decreased susceptibility of peptides toward the proteinases, the resistant mutations always had a beneficial effect on catalytic efficiency. Comparison of the specificity changes obtained for the various substrates suggested that the maximization of the van der Waals contacts between substrate and PR is the major determinant of specificity: the same effect is crucial for inhibitor potency. The natural nucleocapsid/p1 and p1/p6 sites do not appear to be optimized for rapid hydrolysis. Hence, mutation of these rate limiting cleavage sites can partly compensate for the reduced catalytic activity of drug resistant mutant HIV-1 proteinases.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:European Journal Of Biochemistry. - 269 : 16 (2002), p. 4114-4120. -
További szerzők:Weber, Irene T. Bagossi Péter (1966-2011) (biokémikus, vegyész) Boross Péter (1972-) (biokémikus, vegyész) Mahalingam, Bhuvaneshwari Louis, John M. Copeland, Terry D. Torshin, Ivan Y. Harrison, Robert W. Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
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3.

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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4.

001-es BibID:BIBFORM086386
Első szerző:Liu, Fengling
Cím:Analysis of HIV-1 protease mutants to understand mechanisms of resistance / Liu F., Boross Péter, Tőzsér József, Louis J. M., Harrison R. W., Weber I. T.
Dátum:2005
ISSN:1742-464X
Tárgyszavak:Orvostudományok Klinikai orvostudományok idézhető absztrakt
folyóiratcikk
Megjelenés:Febs Journal. - 272 : Suppl1 (2005), p. 12. -
További szerzők:Boross Péter (1972-) (biokémikus, vegyész) Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Louis, John M. Harrison, Robert W. Weber, Irene T.
Pályázati támogatás:OTKA T43482
OTKA
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5.

001-es BibID:BIBFORM040663
Első szerző:Liu, Fengling
Cím:Kinetic, Stability, and Structural Changes in High-resolution Crystal Structures of HIV-1 Protease with Drug-resistant Mutations L24I, I50V, and G73S / Liu Fengling, Boross Peter I., Wang Yuan-Fang, Tozser Jozsef, Louis John M., Harrison Robert W., Weber Irene T.
Dátum:2005
ISSN:0022-2836
Megjegyzések:The crystal structures, dimer stabilities, and kinetics have been analyzed for wild-type human immunodeficiency virus type 1 (HIV-1) protease (PR) and resistant mutants PR(L24I), PR(I50V), and PR(G73S) to gain insight into the molecular basis of drug resistance. The mutations lie in different structural regions. Mutation I50V alters a residue in the flexible flap that interacts with the inhibitor, L24I alters a residue adjacent to the catalytic Asp25, and G73S lies at the protein surface far from the inhibitor-binding site. PR(L24I) and PR(I50V), showed a 4% and 18% lower k(cat)/K(m), respectively, relative to PR. The relative k(cat)/K(m) of PR(G73S) varied from 14% to 400% when assayed using different substrates. Inhibition constants (K(i)) of the antiviral drug indinavir for the reaction catalyzed by the mutant enzymes were about threefold and 50-fold higher for PR(L24I) and PR(I50V), respectively, relative to PR and PR(G73S). The dimer dissociation constant (K(d)) was estimated to be approximately 20 nM for both PR(L24I) and PR(I50V), and below 5 nM for PR(G73S) and PR. Crystal structures of the mutants PR(L24I), PR(I50V) and PR(G73S) were determined in complexes with indinavir, or the p2/NC substrate analog at resolutions of 1.10-1.50 Angstrom. Each mutant revealed distinct structural changes relative to PR. The mutated residues in PR(L24I) and PR(I50V) had reduced intersubunit contacts, consistent with the increased K(d) for dimer dissociation. Relative to PR, PR(I50V) had fewer interactions of Val50 with inhibitors, in agreement with the dramatically increased K(i). The distal mutation G73S introduced new hydrogen bond interactions that can transmit changes to the substrate-binding site and alter catalytic activity. Therefore, the structural alterations observed for drug-resistant mutations were in agreement with kinetic and stability changes.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal Of Molecular Biology. - 354 : 4 (2005), p. 789-800. -
További szerzők:Boross Péter (1972-) (biokémikus, vegyész) Wang, Yuan-Fang Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Louis, John M. Harrison, Robert W. Weber, Irene T.
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6.

001-es BibID:BIBFORM056377
Első szerző:Louis, John M.
Cím:Enhanced stability of monomer fold correlates with extreme drug resistance of HIV-1 protease / John M. Louis, József Tözsér, Julien Roche, Krisztina Matúz, Annie Aniana, Jane M. Sayer
Dátum:2013
ISSN:0006-2960
Megjegyzések:During treatment, mutations in HIV-1 protease (PR) are selected rapidly that confer resistance by decreasing affinity to clinical protease inhibitors (PIs). As these unique drug resistance mutations can compromise the fitness of the virus to replicate, mutations that restore conformational stability and activity while retaining drug resistance are selected on further evolution. Here we identify several compensating mechanisms by which an extreme drug-resistant mutant bearing 20 mutations (PR20) with >5-fold increased Kd and >4000-fold decreased affinity to the PI darunavir functions. (1) PR20 cleaves, albeit poorly, Gag polyprotein substrates essential for viral maturation. (2) PR20 dimer, which exhibits distinctly enhanced thermal stability, has highly attenuated autoproteolysis, thus likely prolonging its lifetime in vivo. (3) The enhanced stability of PR20 results from stabilization of the monomer fold. Both monomeric PR20(T26A) and dimeric PR20 exhibit Tm values 6-7.5 ?C higher than those for their PR counterparts. Two specific mutations in PR20, L33F and L63P at sites of autoproteolysis, increase the Tm of monomeric PR(T26A) by ~8 ?C, similar to PR20(T26A). However, without other compensatory mutations as seen in PR20, L33F and L63P substitutions, together, neither restrict autoproteolysis nor significantly reduce binding affinity to darunavir. To determine whether dimer stability contributes to binding affinity for inhibitors, we examined single-chain dimers of PR and PR(D25N) in which the corresponding identical monomer units were covalently linked by GGSSG sequence. Linking of the subunits did not appreciably change the ?Tm on inhibitor binding; thus stabilization by tethering appears to have little direct effect on enhancing inhibitor affinity.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
HIV-1
Megjelenés:Biochemistry. - 52 : 43 (2013), p. 7678-7688. -
További szerzők:Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Roche, Julien Matúz Krisztina (1980-) (vegyész, biokémikus) Aniana, Annie Sayer, Jane M.
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7.

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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8.

001-es BibID:BIBFORM040664
Első szerző:Louis, John M.
Cím:HIV-I protease : maturation, enzyme specificity, and drug resistance / Louis, J. M., Weber, I. T., Tözsér, J., Clore M. G. , Gronenborn, A. M.
Dátum:2000
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Advances in Pharmacology. - 49 (2000), p. 111-146. -
További szerzők:Weber, Irene T. Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Clore, Marius G. Gronenborn, Angela M.
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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9.

001-es BibID:BIBFORM040670
Első szerző:Mahalingam, Bhuvaneshwari
Cím:Combining mutations in HIV-1 protease to understand mechanisms of resistance / Mahalingam Bhuvaneshwari, Boross Peter, Wang Yuan-Fang, Louis John M., Fischer Christopher C., Tozser Jozsef, Harrison Robert W., Weber Irene T.
Dátum:2002
ISSN:0887-3585
Megjegyzések:HIV-1 develops resistance to protease inhibitors predominantly by selecting mutations in the protease gene. Studies of resistant mutants of HIV-1 protease with single amino acid substitutions have shown a range of independent effects on specificity, inhibition, and stability. Four double mutants, K45I/L90M, K45I/V82S, D30N/V82S, and N88D/L90M were selected for analysis on the basis of observations of increased or decreased stability or enzymatic activity for the respective single mutants. The double mutants were assayed for catalysis, inhibition, and stability. Crystal structures were analyzed for the double mutants at resolutions of 2.2-1.2 A to determine the associated molecular changes. Sequence-dependent changes in protease-inhibitor interactions were observed in the crystal structures. Mutations D30N, K45I, and V82S showed altered interactions with inhibitor residues at P2/P2', P3/P3'/P4/P4', and P1/P1', respectively. One of the conformations of Met90 in K45I/L90M has an unfavorably close contact with the carbonyl oxygen of Asp25, as observed previously in the L90M single mutant. The observed catalytic efficiency and inhibition for the double mutants depended on the specific substrate or inhibitor. In particular, large variation in cleavage of p6(pol)-PR substrate was observed, which is likely to result in defects in the maturation of the protease from the Gag-Pol precursor and hence viral replication. Three of the double mutants showed values for stability that were intermediate between the values observed for the respective single mutants. D30N/V82S mutant showed lower stability than either of the two individual mutations, which is possibly due to concerted changes in the central P2-P2' and S2-S2' sites. The complex effects of combining mutations are discussed.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Proteins-Structure Function And Bioinformatics. - 48 : 1 (2002), p. 107-116. -
További szerzők:Boross Péter (1972-) (biokémikus, vegyész) Wang, Yuan-Fang Louis, John M. Fischer, Christopher C. Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Harrison, Robert W. Weber, Irene T.
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10.

001-es BibID:BIBFORM040668
Első szerző:Mahalingam, Bhuvaneshwari
Cím:Crystal structures of HIV protease V82A and L90M mutants reveal changes in the indinavir-binding site / Mahalingam Bhuvaneshwari, Wang Yuan-Fang, Boross Peter I., Tozser Jozsef, Louis John M., Harrison Robert W., Weber Irene T.
Dátum:2004
ISSN:0014-2956
Megjegyzések:The crystal structures of the wild-type HIV-1 protease (PR) and the two resistant variants, PR(V82A) and PR(L90M), have been determined in complex with the antiviral drug, indinavir, to gain insight into the molecular basis of drug resistance. V82A and L90M correspond to an active site mutation and nonactive site mutation, respectively. The inhibition (K(i)) of PR(V82A) and PR(L90M) was 3.3- and 0.16-fold, respectively, relative to the value for PR. They showed only a modest decrease, of 10-15%, in their k(cat)/K(m) values relative to PR. The crystal structures were refined to resolutions of 1.25-1.4 A to reveal critical features associated with inhibitor resistance. PR(V82A) showed local changes in residues 81-82 at the site of the mutation, while PR(L90M) showed local changes near Met90 and an additional interaction with indinavir. These structural differences concur with the kinetic data.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:European Journal Of Biochemistry. - 271 : 8 (2004), p. 1516-1524. -
További szerzők:Wang, Yuan-Fang Boross Péter (1972-) (biokémikus, vegyész) Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Louis, John M. Harrison, Robert W. Weber, Irene T.
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11.

001-es BibID:BIBFORM003806
Első szerző:Miklóssy Gabriella (biológus, vegyész)
Cím:Novel macromolecular inhibitors of human immunodeficiency virus-l protease / Miklóssy, G., Tőzsér, J., Kádas, J., Ishima, R., Louis, J. M., Bagossi, P.
Dátum:2008
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Protein Engineering, Design and Selection. - 21 : 7 (2008), p. 453-461. -
További szerzők:Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Kádas János (1976-) (molekuláris biológus, biokémikus, kertészmérnök) Ishima, Rieko Louis, John M. Bagossi Péter (1966-2011) (biokémikus, vegyész)
Internet cím:elektronikus változat
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12.

001-es BibID:BIBFORM040679
Első szerző:Tie, Yunfeng
Cím:Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors / Tie Yunfeng, Wang Yuan-Fang, Boross Peter I., Chiu Ting-Yi, Ghosh Arun K., Tozser Jozsef, Louis John M., Harrison Robert W., Weber Irene T.
Dátum:2012
ISSN:0961-8368
Megjegyzések:Clinical inhibitor amprenavir (APV) is less effective on HIV-2 protease (PR₂) than on HIV-1 protease (PR₁). We solved the crystal structure of PR₂ with APV at 1.5 Å resolution to identify structural changes associated with the lowered inhibition. Furthermore, we analyzed the PR₁ mutant (PR(1M) ) with substitutions V32I, I47V, and V82I that mimic the inhibitor binding site of PR₂. PR(1M) more closely resembled PR₂ than PR₁ in catalytic efficiency on four substrate peptides and inhibition by APV, whereas few differences were seen for two other substrates and inhibition by saquinavir (SQV) and darunavir (DRV). High resolution crystal structures of PR(1M) with APV, DRV, and SQV were compared with available PR₁ and PR₂ complexes. Val/Ile32 and Ile/Val47 showed compensating interactions with SQV in PR(1M) and PR₁, however, Ile82 interacted with a second SQV bound in an extension of the active site cavity of PR(1M). Residues 32 and 82 maintained similar interactions with DRV and APV in all the enzymes, whereas Val47 and Ile47 had opposing effects in the two subunits. Significantly diminished interactions were seen for the aniline of APV bound in PR₁ (M) and PR₂ relative to the strong hydrogen bonds observed in PR₁, consistent with 15- and 19-fold weaker inhibition, respectively. Overall, PR(1M) partially replicates the specificity of PR₂ and gives insight into drug resistant mutations at residues 32, 47, and 82. Moreover, this analysis provides a structural explanation for the weaker antiviral effects of APV on HIV-2.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Protein Science. - 21 : 3 (2012), p. 339-350. -
További szerzők:Wang, Yuan-Fang Boross Péter (1972-) (biokémikus, vegyész) Chiu, Ting-Yi Ghosh, Arun K. Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Louis, John M. Harrison, Robert W. Weber, Irene T.
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