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1.

001-es BibID:BIBFORM082814
035-os BibID:(cikkazonosító)e0227062 (WOS)000534341100013 (Scopus)85077691494
Első szerző:Gazda Lívia Diána
Cím:Biochemical characterization of Ty1 retrotransposon protease / Lívia Diána Gazda, Krisztina Joóné Matúz, Tibor Nagy, János András Mótyán, József Tőzsér
Dátum:2020
ISSN:1932-6203
Megjegyzések:Ty1 is one of the many transposons in the budding yeast Saccharomyces cerevisiae. The life-cycle of Ty1 shows numerous similarities with that of retroviruses, e.g. the initially synthesized polyprotein precursor undergoes proteolytic processing by the protease. The retroviral proteases have become important targets of current antiretroviral therapies due to the critical role of the limited proteolysis of Gag-Pol polyprotein in the replication cycle and they therefore belong to the most well-studied enzymes. Comparative analyses of retroviral and retroviral-like proteases can help to explore the key similarities and differences which may help understanding how resistance is developed against protease inhibitors, but the available information about the structural and biochemical characteristics of retroviral-like, and especially retrotransposon, proteases is limited. To investigate the main characteristics of Ty1 retrotransposon protease of Saccharomyces cerevisiae, untagged and His6-tagged forms of Ty1 protease were expressed in E. coli. After purification of the recombinant proteins, activity measurements were performed using synthetic oligopeptide and fluorescent recombinant protein substrates, which represented the wild-type and the modified forms of naturally occurring cleavage sites of the protease. We investigated the dependence of enzyme activity on different reaction conditions (pH, temperature, ionic strength, and urea concentration), and determined enzyme kinetic parameters for the studied substrates. Inhibitory potentials of 10 different protease inhibitors were also tested. Ty1 protease was not inhibited by the inhibitors which have been designed against human immunodeficiency virus type 1 protease and are approved as antiretroviral therapeutics. A quaternary structure of homodimeric Ty1 protease was proposed based on homology modeling, and this structure was used to support interpretation of experimental results and to correlate some structural and biochemical characteristics with that of other retroviral proteases.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
retrotransposon
Ty1
protease
retrovirus
homology modeling
ty1 protease
retroviral protease
retrotransposon protease
yeast
biochemical characterization
Megjelenés:Plos One. - 15 : 1 (2020), p. 1-24. -
További szerzők:Matúz Krisztina (1980-) (vegyész, biokémikus) Nagy Tibor (1988-) (vegyész) Mótyán János András (1981-) (biokémikus, molekuláris biológus) Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Pályázati támogatás:GINOP-2.3.2-15-2016-00044
GINOP
GINOP-2.3.3-15-2016-00021
GINOP
Internet cím:Szerző által megadott URL
DOI
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2.

001-es BibID:BIBFORM086709
035-os BibID:(WoS)000557707400001 (Scopus)85087574382
Első szerző:Golda Mária (molekuláris biológus)
Cím:Biochemical characterization of human retroviral-like aspartic protease 1 (ASPRV1) / Mária Golda, János András Mótyán, Katalin Nagy, Krisztina Matúz, Tibor Nagy, József Tőzsér
Dátum:2020
ISSN:2218-273X
Megjegyzések:The human retroviral-like aspartic protease 1 (ASPRV1) is a mammalian retroviral-like enzyme that catalyzes a critical proteolytic step during epidermal differentiation; therefore, it is also referred as skin-specific aspartic protease (SASPase). Neutrophil granulocytes were also found recently to express ASPRV1 that is involved in the progression of acute chronic in?ammation in the central nervous system, especially in autoimmune encephalomyelitis. Thus, investigation of ASPRV1 is important due to its therapeutic or diagnostic potential. We investigated the structural characteristics of ASPRV1 by homology modeling; analysis of the proposed structure was used for interpretation of in vitro specificity studies. For in vitro characterization, activities of SASP28 and SASP14 enzyme forms were measured using synthetic oligopeptide substrates. We demonstrated that self-processing of SASP28 precursor causes autoactivation of the protease. Highest activity was measured for GST-SASP14 at neutral pH and at high ionic strength, and we proved that pepstatin A and acetyl-pepstatin can also inhibit the protease. In agreement with the structural characteristics, the relatively lower urea dissociation constant implied lower dimer stability of SASP14 compared to that of HIV-1 protease. The obtained structural and biochemical characteristics help better understanding of ASPRV1 function in skin and central nervous system
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
ASPRV1
SASPase
protease
retroviral-like protease
retroviral-like aspartic protease 1
skin-specific aspartic protease
homology modeling
protease inhibitor
Megjelenés:Biomolecules. - 10 : 7 (2020), p. 1-25. -
További szerzők:Mótyán János András (1981-) (biokémikus, molekuláris biológus) Nagy Katalin Matúz Krisztina (1980-) (vegyész, biokémikus) Nagy Tibor (1988-) (vegyész) Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Pályázati támogatás:GINOP-2.3.2-15-2016-00044
GINOP
TÁMOP 4.2.2.A-11/1/KONV-2012-0023
TÁMOP
TÁMOP-4.2.2.D-15/1/KONV-2015-0016
TÁMOP
GINOP-2.3.3-15-2016-00021
GINOP
NKFIH-1150-6/2019
Egyéb
K-101591
OTKA
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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3.

001-es BibID:BIBFORM091549
035-os BibID:(cikkazonosító)127
Első szerző:Kassay Norbert (biotechnológus)
Cím:Biochemical Characterization, Specificity and Inhibition Studies of HTLV-1, HTLV-2, and HTLV-3 Proteases / Kassay Norbert, Mótyán János András, Matúz Krisztina, Golda Mária, Tőzsér József
Dátum:2021
ISSN:2075-1729
Megjegyzések:The human T-lymphotropic viruses (HTLVs) are causative agents of severe diseases including adult T-cell leukemia. Similar to human immunodeficiency viruses (HIVs), the viral protease (PR) plays a crucial role in the viral life-cycle via the processing of the viral polyproteins. Thus, it is a potential target of anti-retroviral therapies. In this study, we performed in vitro comparative analysis of human T-cell leukemia virus type 1, 2, and 3 (HTLV-1, -2, and -3) proteases. Amino acid preferences of S4 to S1· subsites were studied by using a series of synthetic oligopeptide substrates representing the natural and modified cleavage site sequences of the proteases. Biochemical characteristics of the different PRs were also determined, including catalytic efficiencies and dependence of activity on pH, temperature, and ionic strength. We investigated the effects of different HIV-1 PR inhibitors (atazanavir, darunavir, DMP-323, indinavir, ritonavir, and saquinavir) on enzyme activities, and inhibitory potentials of IB-268 and IB-269 inhibitors that were previously designed against HTLV-1 PR. Comparative biochemical analysis of HTLV-1, -2, and -3 PRs may help understand the characteristic similarities and differences between these enzymes in order to estimate the potential of the appearance of drug-resistance against specific HTLV-1 PR inhibitors.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
human T-lymphotropic virus
human T-cell leukemia virus
HTLV
HTLV-1
HTLV-2
HTLV-3
protease
retroviral protease
protease inhibitor
inhibitor
HIV protease inhibitor
Megjelenés:Life. - 11 : 2 (2021), p. 1-21. -
További szerzők:Mótyán János András (1981-) (biokémikus, molekuláris biológus) Matúz Krisztina (1980-) (vegyész, biokémikus) Golda Mária (1986-) (molekuláris biológus) Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Pályázati támogatás:GINOP-2.3.2-15-2016-00044
GINOP
125238
OTKA
TÁMOP 4.2.2.A-11/1/KONV-2012-0023
TÁMOP
TÁMOP-4.2.2.D-15/1/KONV-2015-0016
TÁMOP
TKP2020-IKA-04
Egyéb
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Intézményi repozitóriumban (DEA) tárolt változat
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4.

001-es BibID:BIBFORM038084
Első szerző:Matúz Krisztina (vegyész, biokémikus)
Cím:Inhibition of XMRV and HIV-1 proteases by pepstatin A and acetyl-pepstatin / Matúz Krisztina, Mótyán János András, Li Mi, Wlodawer Alexander, Tőzsér József
Dátum:2012
Megjegyzések:The kinetic properties of two classical inhibitors of aspartic proteases (PRs), pepstatin A and acetyl-pepstatin, were compared in their interactions with HIV-1 and xenotropic murine leukemia virus related virus (XMRV) PRs. Both compounds are substantially weaker inhibitors of XMRV PR than of HIV-1 PR. Previous kinetic and structural studies characterized HIV-1 PR-acetyl-pepstatin and XMRV PR-pepstatin A complexes and suggested dramatically different binding modes. Interaction energies were calculated for the possible binding modes and suggested a strong preference for the one-inhibitor binding mode for HIV-1 PR-acetyl-pepstatin and the two-inhibitor binding mode for XMRV PR-pepstatin A interactions. Comparison of the molecular models suggested that in the case of XMRV PR the relatively unfavorable interactions at S3' and the favorable interactions at S4 and S4' sites with the statine residues may shift the ground state binding towards the two-inhibitor binding mode, whereas the single molecule ground state binding of statines to the HIV-1 PR appear to be more favorable. The preferred single molecular binding to HIV-1 PR allows the formation of the transition state complex, represented by substantially better binding constants. Intriguingly, the crystal structure of the complex of acetyl-pepstatin with XMRV PR has shown a mixed type of binding: the unusual binding mode of two molecules of the inhibitor to the enzyme, in a mode very similar to the previously determined complex with pepstatin A, together with the classical binding mode found for HIV-1 PR. The structure is thus in good agreement with the very similar interaction energies calculated for the two types of binding.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
XMRV protease
Megjelenés:FEBS Journal. - 279 : 17 (2012), p. 3276-3286. -
További szerzők:Mótyán János András (1981-) (biokémikus, molekuláris biológus) Li, Mi Wlodawer, Alexander Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Internet cím:DOI
Intézményi repozitóriumban (DEA) tárolt változat
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5.

001-es BibID:BIBFORM103432
035-os BibID:(cikkazonosító)1888 (WOS)000856936200001 (Scopus)85138336056
Első szerző:Mótyán János András (biokémikus, molekuláris biológus)
Cím:Different Mutation Tolerance of Lentiviral (HIV-1) and Deltaretroviral (BLV and HTLV) Protease Precursors / Mótyán János András, Kassay Norbert, Matúz Krisztina, Tőzsér József
Dátum:2022
ISSN:1999-4915
Megjegyzések:The bovine leukemia virus (BLV) and the human T-lymphothropic viruses (HTLVs) are members of the deltaretrovirus genus of Retroviridae family. An essential event of the retroviral life cycle is the processing of the polyproteins by the viral protease (PR); consequently, these enzymes became important therapeutic targets of the anti-retroviral drugs. As compared to human immunodeficiency viruses (HIVs), the deltaretroviruses have a different replication strategy, as they replicate predominantly in the DNA form, by forcing the infected cell to divide, unlike HIV-1, which replicates mainly by producing a vast number of progeny virions and by reinfection. Due to bypassing the error-prone reverse transcription step of replication, the PRs of deltaretroviruses did not undergo such extensive evolution as HIV PRs and remained more highly conserved. In this work, we studied the abilities of wild-type and modified BLV, HTLV (type 1, 2 and 3), and HIV-1 PRs (fused to an N-terminal MBP tag) for self-processing. We designed a cleavage site mutant MBP-fused BLV PR precursor as well, this recombinant enzyme was unable for self-proteolysis, the MBP fusion tag decreased its catalytic efficiency but showed an unusually low Ki for the IB-268 protease inhibitor. Our results show that the HTLV and BLV deltaretrovirus PRs exhibit lower mutation tolerance as compared to HIV-1 PR, and are less likely to retain their activity upon point mutations at various positions, indicating a higher flexibility of HIV-1 PR in tolerating mutations under selective pressure.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
human T-lymphotropic virus
HTLV
BLV
retroviral protease
autoproteolysis
retrovirus
human immunodeficiency virus
HIV-1
protease
bovine leukemia virus
Megjelenés:Viruses-Basel. - 14 : 9 (2022), p. 1-17. -
További szerzők:Kassay Norbert (1988-) (biotechnológus) Matúz Krisztina (1980-) (vegyész, biokémikus) Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Pályázati támogatás:TKP2021-EGA-20
Egyéb
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Intézményi repozitóriumban (DEA) tárolt változat
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