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1.

001-es BibID:BIBFORM077291
035-os BibID:(WoS)000460412800011 (Scopus)85062658695
Első szerző:Alex, Jimi M.
Cím:Calixarene-mediated assembly of a small antifungal protein / Jimi M. Alex, Martin L. Rennie, Sylvain Engilberge, Gábor Lehoczki, Hajdu Dorottya, Ádám Fizil, Gyula Batta, Peter B. Crowley
Dátum:2019
ISSN:2052-2525
Megjegyzések:Synthetic macrocycles such as calixarenes and cucurbiturils are increasingly applied as mediators of protein assembly and crystallization. The macrocycle can facilitate assembly by providing a surface on which two or more proteins bind simultaneously. This work explores the capacity of the sulfonatocalix[n]arene (sclxn) series to effect crystallization of PAF, a small, cationic antifungal protein. Co-crystallization with sclx4, sclx6 or sclx8 led to highresolution crystal structures. In the absence of sclxn, diffraction-quality crystals of PAF were not obtained. Interestingly, all three sclxn were bound to a similar patch on PAF. The largest and most flexible variant, sclx8, yielded a dimer of PAF. Complex formation was evident in solution via NMR and ITC experiments, showing more pronounced effects with increasing macrocycle size. In agreement with the crystal structure, the ITC data suggested that sclx8 acts as a bidentate ligand. The contributions of calixarene size/conformation to protein recognition and assembly are discussed. Finally, it is suggested that the conserved binding site for anionic calixarenes implicates this region of PAF in membrane binding, which is a prerequisite for antifungal activity.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
conformation selection
molecular glue
nucleating agent
polyethylene glycol
supramolecular chemistry
antifungal proteins
calixarene
Megjelenés:IUCrJ. - 6 : 2 (2019), p. 238-247. -
További szerzők:Rennie, Martin L. Engilberge, Sylvain Lehoczki Gábor (1988-) (biológus, molekuláris biológus) Hajdu Dorottya (1987-) (biológus) Fizil Ádám (1988-) (biológus) Batta Gyula (1953-) (molekula-szerkezet kutató) Crowley, Peter B.
Pályázati támogatás:ANN 110821
OTKA
GINOP-2.3.2-15-2016-00008
GINOP
GINOP-2.3.3-15-2016-00004
GINOP
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2.

001-es BibID:BIBFORM057863
Első szerző:Bereczki Ilona (vegyész, antibiotikumkémikus)
Cím:A few atoms make the difference: Synthetic, CD, NMR and computational studies on antiviral and antibacterial activities of glycopeptide antibiotic aglycon derivatives / Ilona Bereczki, Attila Mandi, Erzsebet Rőth, Aniko Borbás, Adám Fizil, Istvan Komáromi, Attila Sipos, Tibor Kurtán, Gyula Batta, Eszter Ostorhazi, Ferenc Rozgonyi, Evelien Vanderlinden, Lieve Naesens, Ferenc Sztaricskai, Pál Herczegh
Dátum:2015
ISSN:0223-5234
Megjegyzések:Despite the close structural similarity between the heptapeptide cores of the glycopeptide antibiotics teicoplanin and ristocetin, synthetically modified derivatives of their aglycons show significantly different antibacterial and antiviral properties. The teicoplanin aglycon derivatives with one exception proved to be potent antibacterials but they did not exhibit anti-influenza virus activity. In contrast, the aglycoristocetin derivatives generally showed high anti-influenza virus activity and possessed moderate antibacterial activity. A systematic structure-activity relationship study has been carried out on ristocetin and teicoplanin aglycon derivatives, to explore which structural differences are responsible for these markedly different biological activities. According to electronic circular dichroism and in silico conformational studies, it was found that the differences in anti-influenza virus activity are mainly determined by the conformation of the heptapeptide core of the antibiotics controlled by the presence or absence of chloro substituents. Knowledge of the bioactive conformation will help to design new analogs with improved anti-influenza virus activity. For the teicoplanin derivatives, it was shown that derivatization to improve the antiviral efficacy was accompanied by a significant decrease in antibacterial activity.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Teicoplanin aglycon
Ristocetin aglycon
Antibacterial
Antiviral
Conformation
Megjelenés:European Journal of Medicinal Chemistry. - 94 (2015), p. 73-86. -
További szerzők:Mándi Attila (1981-) (vegyész, német szakfordító) Rőth Erzsébet (1957-) (vegyész) Borbás Anikó (1965-) (vegyész) Fizil Ádám (1988-) (biológus) Komáromi István (1957-) (vegyész, molekuláris biológus, biokémikus) Sipos Attila (1977-) (vegyész, angol-magyar szakfordító) Kurtán Tibor (1973-) (vegyész, angol szakfordító) Batta Gyula (1953-) (molekula-szerkezet kutató) Ostorházi Eszter (1978-) (mikrobiológus) Rozgonyi Ferenc (1938-) (biológus, mikrobiológus) Vanderlinden, Evelien Naesens, Lieve (1965-) (kémikus) Sztaricskai Ferenc (1934-2012) (vegyész, antibiotikum-kémikus) Herczegh Pál (1947-) (vegyész, antibiotikumkémikus)
Pályázati támogatás:K 109208, K105871
OTKA
NIIFI 10038
Egyéb
TÁMOP-4.2.4.A/2-11-1-2012-0001
TÁMOP
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3.

001-es BibID:BIBFORM058875
Első szerző:Binder, Ulrike
Cím:Protein kinase A signaling and calcium ions are major players in PAF mediated toxicity against Aspergillus niger / Ulrike Binder, Mojca Benčina, Ádám Fizil, Gyula Batta, Anil K. Chhillar, Florentine Marx
Dátum:2015
ISSN:0014-5793 1873-3468
Megjegyzések:The Penicillium chrysogenum antifungal protein PAF is toxic against potentially pathogenic Ascomycetes. We used the highly sensitive aequorin-expressing model Aspergillus niger to identify a defined change in cytoplasmic free Ca2+ dynamics in response to PAF. This Ca2+ signature depended on an intact positively charged lysine-rich PAF motif. By combining Ca2+ measurements in A. niger mutants with deregulated cAMP/protein kinase A (PKA) signaling, we proved the interconnection of Ca2+ perturbation and cAMP/PKA signaling in the mechanistic function of PAF. A deep understanding of the mode of action of PAF is an invaluable prerequisite for its future application as new antifungal drug.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Antifungal protein
PAF
Aspergillus niger
Calcium homeostasis
Protein kinase A signaling
Megjelenés:Febs Letters. - 589 : 11 (2015), p. 1266-1271. -
További szerzők:Bencina, Mojca Fizil Ádám (1988-) (biológus) Batta Gyula (1953-) (molekula-szerkezet kutató) Chhillar, Anil Kumar Marx, Florentine
Pályázati támogatás:ANN 110821
OTKA
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4.

001-es BibID:BIBFORM106470
035-os BibID:(cikkazonosító)1208 (WoS)000915651700001 (Scopus)85146742732
Első szerző:Czajlik András (gyógyszerész)
Cím:DMSO-Induced Unfolding of the Antifungal Disulfide Protein PAF and Its Inactive Variant: A Combined NMR and DSC Study / András Czajlik, Ágnes Batta, Kinga Kerner, Ádám Fizil, Dorottya Hajdu, Mária Raics, Katalin E. Kövér, Gyula Batta
Dátum:2023
ISSN:1422-0067
Megjegyzések:PAF and related antifungal proteins are promising antimicrobial agents. They have highly stable folds around room temperature due to the presence of 3-4 disulfide bonds. However, unfolded states persist and contribute to the thermal equilibrium in aqueous solution, and low-populated states might influence their biological impact. To explore such equilibria during dimethyl sulfoxide (DMSO)-induced chemical unfolding, we studied PAF and its inactive variant PAFD19S using nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC). According to the NMR monitoring at 310 K, the folded structures disappear above 80 v/v% DMSO concentration, while the unfolding is completely reversible. Evaluation of a few resolved peaks from viscosity-compensated 15N-1H HSQC spectra of PAF yielded G = 23 ± 7 kJ/M as the average value for NMR unfolding enthalpy. The NMR-based structures of PAF and the mutant in 50 v/v% DMSO/H2O mixtures were more similar in the mixed solvents then they were in water. The 15N NMR relaxation dynamics in the same mixtures verified the rigid backbones of the NMR-visible fractions of the proteins; still, enhanced dynamics around the termini and some loops were observed. DSC monitoring of the Tm melting point showed parabolic dependence on the DMSO molar fraction and suggested that PAF is more stable than the inactive PAFD19S. The DSC experiments were irreversible due to the applied broad temperature range, but still suggestive of the endothermic unfolding of PAF.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
antifungal protein
PAF
disulfide bond
DMSO-induced unfolding
nuclear magnetic resonance (NMR)
differential scanning calorimetry (DSC)
Megjelenés:International Journal Of Molecular Sciences. - 24 : 2 (2023), p. 1-13. -
További szerzők:Batta Ágnes Kerner Kinga Fizil Ádám (1988-) (biológus) Hajdu Dorottya (1987-) (biológus) Hadháziné Raics Mária (1991-) (vegyész) Kövér Katalin, E. (1956-2023) (vegyész) Batta Gyula (1953-) (molekula-szerkezet kutató)
Pályázati támogatás:TKP2020-NKA-11
Egyéb
NN 128368
OTKA
GINOP-2.3.2-15-2016-00008
GINOP
GINOP-2.3.3-15-2016-00004
GINOP
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Intézményi repozitóriumban (DEA) tárolt változat
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5.

001-es BibID:BIBFORM076180
035-os BibID:(cikkazonosító)e0204825 (WOS)000447417900013 (Scopus)85055079512
Első szerző:Fizil Ádám (biológus)
Cím:Calcium binding of the antifungal protein PAF: Structure, dynamics and function aspects by NMR and MD simulations / Ádám Fizil, Christoph Sonderegger, András Czajlik, Attila Fekete, István Komáromi, Dorottya Hajdu, Florentine Marx, Gyula Batta
Dátum:2018
ISSN:1932-6203
Megjegyzések:Calcium ions (Ca2+) play an important role in the toxicity of the cysteine-rich and cationic antifungal protein PAF from Penicillium chrysogenum: high extracellular Ca2+ levels reduce the toxicity of PAF in the sensitive model fungus Neurospora crassa in a concentration dependent way. However, little is known about the mechanistic details of the Ca2+ ion impact and the Ca2+ binding capabilities of PAF outside the fungal cell, which might be the reason for the activity loss. Using nuclear magnetic resonance (NMR), isothermal titration calorimetry and molecular dynamics (MD) simulations we demonstrated that PAF weakly, but specifically binds Ca2+ ions. MD simulations of PAF predicted one major Ca2+ binding site at the C-terminus involving Asp53 and Asp55, while Asp19 was considered as putative Ca2+ binding site. The exchange of Asp19 to serine had little impact on the Ca2+ binding, however caused the loss of antifungal activity, as was shown in our recent study. Now we replaced the C-terminal aspartates and expressed the serine variant PAF{D53S/D55S}. The specific Ca2+ binding affinity of PAF{D53S/D55S} decreased significantly if compared to PAF, whereas the antifungal activity was retained. To understand more details of Ca2+ interactions, we investigated the NMR and MD structure/dynamics of the free and Ca2+-bound PAF and PAF{D53S/D55S}. Though we found some differences between these protein variants and the Ca2+ complexes, these effects cannot explain the observed Ca2+ influence. In conclusion, PAF binds Ca2+ ions selectively at the C-terminus; however, this Ca2+ binding does not seem to play a direct role in the previously documented modulation of the antifungal activity of PAF.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Plos One. - 13 : 10 (2018), p. 1-19. -
További szerzők:Sonderegger, Christoph Czajlik András (1975-) (gyógyszerész) Fekete Attila (1983-) (vegyész) Komáromi István (1957-) (vegyész, molekuláris biológus, biokémikus) Hajdu Dorottya (1987-) (biológus) Marx, Florentine Batta Gyula (1953-) (molekula-szerkezet kutató)
Pályázati támogatás:ANN 110821
OTKA
TÁMOP-4.2.1/B-09/1/KONV-2010-0007
TÁMOP
GINOP-2.3.2-15-2016-00008
GINOP
GINOP-2.3.3-15-2016-00004
GINOP
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6.

001-es BibID:BIBFORM071610
Első szerző:Fizil Ádám (biológus)
Cím:Egy gombaellenes gombafehérje : PAF, a bűvös hatóanyag / Fizil Ádám, Gáspári Zoltán, Batta Gyula
Dátum:2017
ISSN:0040-3717
Tárgyszavak:Természettudományok Kémiai tudományok ismeretterjesztő, népszerűsítő cikk
Megjelenés:Természet világa. - 148 : 6 (2017), p. 265-268. -
További szerzők:Gáspári Zoltán Batta Gyula (1953-) (molekula-szerkezet kutató)
Pályázati támogatás:NKFI ANN110821
Egyéb
NKFI NF104198
Egyéb
GINOP-2.3.2-15-2016-00008
GINOP
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
Szerző által megadott URL
Szerző által megadott URL
Borító:

7.

001-es BibID:BIBFORM058525
Első szerző:Fizil Ádám (biológus)
Cím:"Invisible" Conformers of an Antifungal Disulfide Protein Revealed by Constrained Cold and Heat Unfolding, CEST-NMR Experiments, and Molecular Dynamics Calculations / Ádám Fizil, Zoltán Gáspári, Terézia Barna, Florentine Marx, Gyula Batta
Dátum:2015
ISSN:0947-6539
Megjegyzések:Transition between conformational states in proteins is being recognized as a possible key factor of function. In support of this, hidden dynamic NMR structures were detected in several cases up to populations of a few percent. Here, we show by two- and three-state analysis of thermal unfolding, that the population of hidden states may weight 20?40?% at 298 K in a disulfide-rich protein. In addition, sensitive 15N-CEST NMR experiments identified a low populated (0.15?%) state that was in slow exchange with the folded PAF protein. Remarkably, other techniques failed to identify the rest of the NMR "dark matter". Comparison of the temperature dependence of chemical shifts from experiments and molecular dynamics calculations suggests that hidden conformers of PAF differ in the loop and terminal regions and are most similar in the evolutionary conserved core. Our observations point to the existence of a complex conformational landscape with multiple conformational states in dynamic equilibrium, with diverse exchange rates presumably responsible for the completely hidden nature of a considerable fraction.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
conformation analysis
molecular modeling
MR spectroscopy
protein folding
protein structures
Megjelenés:Chemistry-A European Journal 21 : 13 (2015), p. 5136-5144. -
További szerzők:Gáspári Zoltán Barna Teréz (1963-) (vegyész) Marx, Florentine Batta Gyula (1953-) (molekula-szerkezet kutató)
Pályázati támogatás:TÁMOP-4.2.4.A/2-11-1-2012-0001
TÁMOP
TÁMOP-4.2.1.B-11/2/KMR-2011-0002
TÁMOP
NF 104198, ANN 110821, K 105459
OTKA
NIIFI 10038
Egyéb
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8.

001-es BibID:BIBFORM077292
035-os BibID:(WoS)000466621200053 (Scopus)85061541042
Első szerző:Hajdu Dorottya (biológus)
Cím:Solution structure and novel insights into phylogeny and mode of action of the Neosartorya (Aspergillus) fischeri antifungal protein (NFAP) / Hajdu Dorottya, Huber Anna, Czajlik András, Tóth Liliána, Kele Zoltán, Kocsubé Sándor, Fizil Ádám, Marx Florentine, Galgóczy László, Batta Gyula
Dátum:2019
ISSN:0141-8130
Megjegyzések:Small, cysteine-rich and cationic antifungal proteins fromnatural sources are promising candidates for the development of novel treatment strategies to prevent and combat infections caused by drug-resistant fungi. However, limited information about their structure and antifungal mechanism hampers their future applications. In the present study, we determined the solution structure, dynamics and associated solvent areas of the Neosartorya (Aspergillus) fischeri antifungal protein NFAP. Genome mining within the genus revealed the presence of orthologous genes in N. fischeri and Neosartorya spathulata, and genes encoding closely related proteins can be found in Penicillium brasiliensis and Penicillium oxalicum. We show that the tertiary structure of these putative proteins can be resolved using the structure of NFAP as reliable template for in silico prediction. Localization studies with fluorescence-labelled protein pointed at an energy-dependent uptake mechanism of NFAP in the sensitive model fungus Neurospora crassa and subsequent cytoplasmic localization coincided with cell-death induction. The presented results contribute to a better understanding of the structure/function relationship of NFAP and related proteins and pave the way towards future antifungal drug development.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Neosartorya (Aspergillus) fischeri antifungal
protein (NFAP)
Nuclear magnetic resonance (NMR)
Antifungal mechanism
Megjelenés:International Journal of Biological Macromolecules. - 129 (2019), p. 511-522.
További szerzők:Huber Anna Czajlik András (1975-) (gyógyszerész) Tóth Liliána Kele Zoltán Kocsubé Sándor Fizil Ádám (1988-) (biológus) Marx, Florentine Galgóczy László (1950-) Batta Gyula (1953-) (molekula-szerkezet kutató)
Pályázati támogatás:GINOP-2.3.2-15-2016-00008
GINOP
GINOP-2.3.3-15-2016-00004
GINOP
PD 120808
OTKA
ANN 122833
OTKA
ANN 110821
OTKA
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9.

001-es BibID:BIBFORM072198
035-os BibID:(Cikkazonosító)1751 (WOS)000423429800003 (Scopus)85041371349
Első szerző:Huber Anna
Cím:New Antimicrobial Potential and Structural Properties of PAFB: A Cationic, Cysteine-Rich Protein from Penicillium chrysogenum Q176 / Anna Huber, Dorottya Hajdu, Doris Bratschun-Khan, Zoltán Gáspári, Mihayl Varbanov, Stéphanie Philippot, Ádám Fizil, András Czajlik, Zoltán Kele, Christoph Sonderegger, László Galgóczy, Andrea Bodor, Florentine Marx, Gyula Batta
Dátum:2018
ISSN:2045-2322
Megjegyzések:Small, cysteine-rich and cationic proteins with antimicrobial activity are produced by diverse organisms of all kingdoms and represent promising molecules for drug development. The ancestor of all industrial penicillin producing strains, the ascomycete Penicillium chryosgenum Q176, secretes the extensively studied antifungal protein PAF. However, the genome of this strain harbours at least two more genes that code for other small, cysteine-rich and cationic proteins with potential antifungal activity. In this study, we characterized the pafB gene product that shows high similarity to PgAFP from P. chrysogenum R42C. Although abundant and timely regulated pafB gene transcripts were detected, we could not identify PAFB in the culture broth of P. chrysogenum Q176. Therefore, we applied a P. chrysogenum-based expression system to produce sufficient amounts of recombinant PAFB to address unanswered questions concerning the structure and antimicrobial function. Nuclear magnetic resonance (NMR)-based analyses revealed a compact [beta]-folded structure, comprising five [beta]-strands connected by four solvent exposed and flexible loops and an "abcabc" disulphide bond pattern. We identified PAFB as an inhibitor of growth of human pathogenic moulds and yeasts. Furthermore, we document for the first time an anti-viral activity for two members of the small, cysteine-rich and cationic protein group from ascomycetes.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Scientific Reports. - 8 : 1 (2018), p. 1751. -
További szerzők:Hajdu Dorottya (1987-) (biológus) Bratschun-Khan, Doris Gáspári Zoltán Varbanov, Mihayl Philippot, Stéphanie Fizil Ádám (1988-) (biológus) Czajlik András (1975-) (gyógyszerész) Kele Zoltán Sonderegger, Christoph Galgóczy László (1950-) Bodor Andrea Marx, Florentine Batta Gyula (1953-) (molekula-szerkezet kutató)
Pályázati támogatás:ANN 110821
OTKA
GINOP-2.3.2-15-2016-00008
GINOP
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10.

001-es BibID:BIBFORM066900
Első szerző:Sonderegger, Christoph
Cím:A Penicillium chrysogenum-based expression system for the production of small, cysteine-rich antifungal proteins for structural and functional analyses / Christoph Sonderegger, László Galgóczy, Sandra Garrigues, Ádám Fizil, Attila Borics, Paloma Manzanares, Nikoletta Hegedüs, Anna Huber, Jose F. Marcos, Gyula Batta, Florentine Marx
Dátum:2016
ISSN:1475-2859
Megjegyzések:Small, cysteine-rich and cationic antifungal proteins (APs) from filamentous ascomycetes, such as NFAP from Neosartorya fischeri and PAF from Penicillium chrysogenum, are promising candidates for novel drug development. A prerequisite for their application is a detailed knowledge about their structure-function relation and mode of action, which would allow protein modelling to enhance their toxicity and specificity. Technologies for structure analyses, such as electronic circular dichroism (ECD) or NMR spectroscopy, require highly purified samples and in case of NMR milligrams of uniformly 15N-/13C-isotope labelled protein. To meet these requirements, we developed a P. chrysogenum-based expression system that ensures sufficient amount and optimal purity of APs for structural and functional analyses.RESULTS:The APs PAF, PAF mutants and NFAP were expressed in a P. chrysogenum ?paf mutant strain that served as perfect microbial expression factory. This strain lacks the paf-gene coding for the endogenous antifungal PAF and is resistant towards several APs from other ascomycetes. The expression of the recombinant proteins was under the regulation of the strong paf promoter, and the presence of a paf-specific pre-pro sequence warranted the secretion of processed proteins into the supernatant. The use of defined minimal medium allowed a single-step purification of the recombinant proteins. The expression system could be extended to express PAF in the related fungus Penicillium digitatum, which does not produce detectable amounts of APs, demonstrating the versatility of the approach. The molecular masses, folded structures and antifungal activity of the recombinant proteins were analysed by ESI-MS, ECD and NMR spectroscopy and growth inhibition assays.CONCLUSION:This study demonstrates the implementation of a paf promoter driven expression cassettes for the production of cysteine-rich, cationic, APs in different Penicillium species. The system is a perfect tool for the generation of correctly folded proteins with high quality for structure-function analyses.KEYWORDS:Antifungal proteins; Electronic circular dichroism (ECD) spectroscopy; NFAP; Neosartorya fischeri; Nuclear magnetic resonance (NMR); PAF; Penicillium chrysogenum; Penicillium digitatum; Recombinant protein production
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Microbial Cell Factories 15 : 192 (2016), p. 1-14. -
További szerzők:Galgóczy László (1950-) Garrigues, Sandra Fizil Ádám (1988-) (biológus) Borics Attila Manzanares, Paloma Hegedűs Nikoletta Huber Anna Marcos, Jose F. Batta Gyula (1953-) (molekula-szerkezet kutató) Marx, Florentine
Pályázati támogatás:ANN110821
OTKA
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Intézményi repozitóriumban (DEA) tárolt változat
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11.

001-es BibID:BIBFORM066897
035-os BibID:(cikkazonosító)e0169920 (WOS)000391844200058 (Scopus)85009084271
Első szerző:Sonderegger, Christoph
Cím:D19S Mutation of the Cationic, Cysteine-Rich Protein PAF: Novel Insights into Its Structural Dynamics, Thermal Unfolding and Antifungal Function / Christoph Sonderegger, Ádám Fizil, Laura Burtscher, Dorottya Hajdu, Alberto Muñoz, Zoltán Gaáspári, Nick D. Read, Gyula Batta, Florentine Marx
Dátum:2017
ISSN:1932-6203
Megjegyzések:The cysteine-rich, cationic, antifungal protein PAF is abundantly secreted into the culture supernatant of the filamentous Ascomycete Penicillium chrysogenum. The five ?-strands of PAF form a compact ?-barrel that is stabilized by three disulphide bonds. The folding of PAF allows the formation of four surface-exposed loops and distinct charged motifs on the protein surface that might regulate the interaction of PAF with the sensitive target fungus. The growth inhibitory activity of this highly stable protein against opportunistic fungal pathogens provides great potential in antifungal drug research. To understand its mode of action, we started to investigate the surface-exposed loops of PAF and replaced one aspartic acid at position 19 in loop 2 that is potentially involved in PAF active or binding site, with a serine (Asp19 to Ser19). We analysed the overall effects, such as unfolding, electrostatic changes, sporadic conformers and antifungal activity when substituting this specific amino acid to the fairly indifferent amino acid serine. Structural analyses revealed that the overall 3D solution structure is virtually identical with that of PAF. However, PAFD19S showed slightly increased dynamics and significant differences in the surface charge distribution. Thermal unfolding identified PAFD19S to be rather a two-state folder in contrast to the three-state folder PAF. Functional comparison of PAFD19S and PAF revealed that the exchange at residue 19 caused a dramatic loss of antifungal activity: the binding and internalization of PAFD19S by target cells was reduced and the protein failed to trigger an intracellular Ca2+ response, all of which are closely linked to the antifungal toxicity of PAF. We conclude that the negatively charged residue Asp19 in loop 2 is essential for full function of the cationic protein PAF.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Plos One. - 12 : 1 (2017), p. e0169920-1 - e0169920-21. -
További szerzők:Fizil Ádám (1988-) (biológus) Burtscher, Laura Hajdu Dorottya (1987-) (biológus) Munoz, Alberto Gaáspári Zoltán Read, Nick D. Batta Gyula (1953-) (molekula-szerkezet kutató) Marx, Florentine
Pályázati támogatás:ANN110821
OTKA
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
Borító:

12.

001-es BibID:BIBFORM109184
035-os BibID:(Scopus)85149121543 (WoS)000939526000001
Első szerző:Váradi Györgyi
Cím:Confirmation of the Disulfide Connectivity and Strategies for Chemical Synthesis of the Four-Disulfide-Bond-Stabilized Aspergillus giganteus Antifungal Protein, AFP / Györgyi Váradi, Gyula Batta, László Galgóczy, Dorottya Hajdu, Ádám Fizil, András Czajlik, Máté Virágh, Zoltán Kele, Vera Meyer, Sascha Jung, Florentine Marx, Gábor K. Tóth
Dátum:2023
ISSN:0163-3864 1520-6025
Megjegyzések:Emerging fungal infections require new, more efficient antifungal agents and therapies. AFP, a protein from Aspergillus giganteus with four disulfide bonds, is a promising candidate because it selectively inhibits the growth of filamentous fungi. In this work, the reduced form of AFP was prepared using native chemical ligation. The native protein was synthesized via oxidative folding with uniform protection for cysteine thiols. AFP's biological activity depends heavily on the pattern of natural disulfide bonds. Enzymatic digestion and MS analysis provide proof for interlocking disulfide topology (abcdabcd) that was previously assumed. With this knowledge, a semi-orthogonal thiol protection method was designed. By following this strategy, out of a possible 105, only 6 disulfide isomers formed and 1 of them proved to be identical with the native protein. This approach allows the synthesis of analogs for examining structure-activity relationships and, thus, preparing AFP variants with higher antifungal activity.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Journal of Natural Products. - 86 : 4 (2023), p. 782-790. -
További szerzők:Batta Gyula (1953-) (molekula-szerkezet kutató) Galgóczy László (1950-) Hajdu Dorottya (1987-) (biológus) Fizil Ádám (1988-) (biológus) Czajlik András (1975-) (gyógyszerész) Virágh Máté Kele Zoltán Meyer, Vera Jung, Sascha Marx, Florentine Tóth Gábor K.
Pályázati támogatás:NKFIH TKP2021-EGA-32
Egyéb
NKFIH FK 134343
Egyéb
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
Borító:
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