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1.

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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2.

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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3.

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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4.

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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5.

001-es BibID:BIBFORM040678
Első szerző:Tie, Yunfeng
Cím:Molecular basis for substrate recognition and drug resistance from 1.1 to 1.6 A angstroms resolution crystal structures of HIV-1 protease mutants with substrate analogs / Tie Yunfeng, Boross Peter I., Wang Yuan-Fang, Gaddis Laquasha, Liu Fengling, Chen Xianfeng, Tozser Jozsef, Harrison Robert W., Weber Irene T.
Dátum:2005
ISSN:1742-464X
Megjegyzések:HIV-1 protease (PR) and two drug-resistant variants--PR with the V82A mutation (PR(V82A)) and PR with the I84V mutation (PR(I84V))--were studied using reduced peptide analogs of five natural cleavage sites (CA-p2, p2-NC, p6pol-PR, p1-p6 and NC-p1) to understand the structural and kinetic changes. The common drug-resistant mutations V82A and I84V alter residues forming the substrate-binding site. Eight crystal structures were refined at resolutions of 1.10-1.60 A. Differences in the PR-analog interactions depended on the peptide sequence and were consistent with the relative inhibition. Analog p6(pol)-PR formed more hydrogen bonds of P2 Asn with PR and fewer van der Waals contacts at P1' Pro compared with those formed by CA-p2 or p2-NC in PR complexes. The P3 Gly in p1-p6 provided fewer van der Waals contacts and hydrogen bonds at P2-P3 and more water-mediated interactions. PR(I84V) showed reduced van der Waals interactions with inhibitor compared with PR, which was consistent with kinetic data. The structures suggest that the binding affinity for mutants is modulated by the conformational flexibility of the substrate analogs. The complexes of PR(V82A) showed smaller shifts of the main chain atoms of Ala82 relative to PR, but more movement of the peptide analog, compared to complexes with clinical inhibitors. PR(V82A) was able to compensate for the loss of interaction with inhibitor caused by mutation, in agreement with kinetic data, but substrate analogs have more flexibility than the drugs to accommodate the structural changes caused by mutation. Hence, these structures help to explain how HIV can develop drug resistance while retaining the ability of PR to hydrolyze natural substrates.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Febs Journal. - 272 : 20 (2005), p. 5265-5277. -
További szerzők:Boross Péter (1972-) (biokémikus, vegyész) Wang, Yuan-Fang Gaddis, Laquasha Liu, Fengling Chen, Xianfeng Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Harrison, Robert W. Weber, Irene T.
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6.

001-es BibID:BIBFORM001504
Első szerző:Tie, Yunfeng
Cím:Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir / Tie Y., Kovalevsky A. Y., Boross P., Wang Y. F., Ghosh A. K., Tozser J., Harrison R. W., Weber I. T.
Dátum:2007
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Proteins 67 : 1 (2007), p. 232-242. -
További szerzők:Kovalevsky, Andrey Yu Boross Péter (1972-) (biokémikus, vegyész) Wang, Yuan-Fang Ghosh, Arun K. Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Harrison, Robert W. Weber, Irene T.
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7.

001-es BibID:BIBFORM001533
Első szerző:Wang, Yuan-Fang
Cím:Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease / Wang, Y. F., Tie, Y., Boross P. I., Tőzsér J., Ghosh, A. K., Harrison, R. W., Weber, I. T.,
Dátum:2007
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal of Medicinal Chemistry 50 : 18 (2007), p. 4509-4515. -
További szerzők:Tie, Yunfeng Boross Péter (1972-) (biokémikus, vegyész) Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Ghosh, Arun K. Harrison, Robert W. Weber, Irene T.
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