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1.

001-es BibID:BIBFORM031410
035-os BibID:PMID:17442645 WOS:000246867300007
Első szerző:Chuluunbaatar, Tungalag
Cím:An EcoRI-RsrI chimeric restriction endonuclease retains parental sequence specificity / Tungalag Chuluunbaatar, Tetiana Ivanenko-Johnston, Mónika Fuxreiter, Ruslan Meleshko, Tamás Raskó, István Simon, Joseph Heitman, Antal Kiss
Dátum:2007
ISSN:1570-9639
Megjegyzések:o test their structural and functional similarity, hybrids were constructed between EcoRI and RsrI, two restriction endonucleases recognizing the same DNA sequence and sharing 50% amino acid sequence identity. One of the chimeric proteins (EERE), in which the EcoRI segment His147-Ala206 was replaced with the corresponding RsrI segment, showed EcoRI/RsrI-specific endonuclease activity. EERE purified from inclusion bodies was found to have approximately 100-fold weaker activity but higher specific DNA binding affinity, than EcoRI. Increased binding is consistent with results of molecular dynamics simulations, which indicate that the number of hydrogen bonds formed with the recognition sequence increased in the chimera as compared to EcoRI. The success of obtaining an EcoRI-RsrI hybrid endonuclease, which differs from EcoRI by 22 RsrI-specific amino acid substitutions and still preserves canonical cleavage specificity, is a sign of structural and functional similarity shared by the parental enzymes. This conclusion is also supported by computational studies, which indicate that construction of the EERE chimera did not induce substantial changes in the structure of EcoRI. Surprisingly, the chimeric endonuclease was more toxic to cells not protected by EcoRI methyltransferase, than the parental EcoRI mutant. Molecular modelling revealed structural alterations, which are likely to impede coupling between substrate recognition and cleavage and suggest a possible explanation for the toxic phenotype.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:Biochimica et Biophysica Acta (BBA). Proteins and Proteomics. - 1774 : 5 (2007), p. 583-594. -
További szerzők:Ivanenko-Johnston, Tetiana Fuxreiter Mónika (1969-) (kutató vegyész) Meleshko, Ruslan Raskó Tamás Simon István Heitman, Joseph Kiss Antal (MTA, Szeged)
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2.

001-es BibID:BIBFORM055232
035-os BibID:Article ID: e24157
Első szerző:Dunker, A. Keith
Cím:What's in a name? : Why these proteins are intrinsically disordered / A. Keith Dunker, M. Madan Babu, Elisar Barbar, Martin Blackledge, Sarah E. Bondos, Zsuzsanna Dosztányi, H. Jane Dyson, Julie Forman-Kay, Monika Fuxreiter, Jörg Gsponer, Kyou-Hoon Han, David T. Jones, Sonia Longhi, Steven J. Metallo, Ken Nishikawa, Ruth Nussinov, Zoran Obradovic, Rohit V. Pappu, Burkhard Rost, Philipp Selenko, Vinod Subramaniam, Joel L. Sussman, Peter Tompa, Vladimir N. Uversky
Dátum:2013
ISSN:2169-0693 2169-0707
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény hazai lapban
Megjelenés:Intrinsically Disordered Proteins. - 1 : 1 (2013), [5] p. -
További szerzők:Babu, M. Madan Barbar, Elisar Blackledge, Martin Bondos, Sarah E. Dosztányi Zsuzsanna Dyson, H. Jane Forman-Kay, Julie Fuxreiter Mónika (1969-) (kutató vegyész) Gsponer, Joerg Han, Kyou-Hoon Jones, David T. W. Longhi, Sonia Metallo, Steven J. Nishikawa, Ken Nussinov, Ruth Obradovic, Zoran Pappu, Rohit V. Rost, Burkhard Selenko, Philipp Subramaniam, Vinod Sussman, Joel L. Tompa Péter Uversky, Vladimir N.
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3.

001-es BibID:BIBFORM031413
035-os BibID:PMID:9188736 WOS:A1997XD03700007
Első szerző:Fuxreiter Mónika (kutató vegyész)
Cím:Role of electrostatics at the catalytic metal binding site in xylose isomerase action : Ca(2+)-inhibition and metal competence in the double mutant D254E/D256E / Fuxreiter M., Bocskei Z., Szeibert A., Szabo E., Dallmann G., Naray-Szabo G., Asboth B.
Dátum:1997
ISSN:0887-3585
Megjegyzések:The catalytic metal binding site of xylose isomerase from Arthrobacter B3728 was modified by protein engineering to diminish the inhibitory effect of Ca2+ and to study the competence of metals on catalysis. To exclude Ca2+ from Site 2 a double mutant D254E/D256E was designed with reduced space available for binding. In order to elucidate structural consequences of the mutation the binary complex of the mutant with Mg2+ as well as ternary complexes with bivalent metal ions and the open-chain inhibitor xylitol were crystallized for x-ray studies. We determined the crystal structures of the ternary complexes containing Mg2+, Mn2+, and Ca2+ at 2.2 to 2.5 Angstrom resolutions, and refined them to R factors of 16.3, 16.6, and 19.1, respectively. We found that all metals are liganded by both engineered glutamates as well as by atoms O1 and O2 of the inhibitor. The similarity of the coordination of Ca2+ to that of the cofactors as well as results with Be2+ weaken the assumption that geometry differences should account for the catalytic noncompetence of this ion. Kinetic results of the D254E/D256E mutant enzyme showed that the significant decrease in Ca2+ inhibition was accompanied by a similar reduction in the enzymatic activity. Qualitative argumentation, based on the protein electrostatic potential, indicates that the proximity of the negative side chains to the substrate significantly reduces the electrostatic stabilization of the transition state. Furthermore, due to the smaller size of the catalytic metal site, no water molecule, coordinating the metal, could be observed in ternary complexes of the double mutant. Consequently, the proton shuttle step in the overall mechanism should differ from that in the wild type. These effects can account for the observed decrease in catalytic efficiency of the D254E/D256E mutant enzyme.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:Proteins. - 28 : 2 (1997), p. 183-193. -
További szerzők:Szeibert A. Szabó E. Dallmann, G. Náray-Szabó Gábor Asboth, B. Böcskei Z.
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4.

001-es BibID:BIBFORM031401
035-os BibID:WOS:000176646100018 PMID:12112699
Első szerző:Fuxreiter Mónika (kutató vegyész)
Cím:Role of stabilization centers in 4 helix bundle proteins / M. Fuxreiter, I. Simon
Dátum:2002
ISSN:0887-3585
Megjegyzések:Stabilization centers (SCs) were shown to play an important role in preventing decay of three-dimensional protein structures. These residue clusters, stabilized by cooperative long-range interactions, were proposed to serve as anchoring points for arranging secondary structure elements. In all-alpha proteins, SC elements appear less frequently than in all-beta, alpha/beta, and alpha+beta proteins suggesting that tertiary structure formation of all-alpha proteins is governed by different principles than in other protein classes. Here we analyzed the relation between the formation of stabilization centers and the interaxial angles (Omega) of a-helices in 4 helix bundle proteins. In the distance range, where dipoles have dominant effect on the helix pair arrangement, those helix pairs, where residues from both helices participate in SC elements, appear as parallel more frequently than those helices where no SC elements are present. For SC containing helix pairs, the energetic difference between the parallel and antiparallel states decreases considerably from 1.1 kcal/mol to 0.4 kcal/mol. Although the observed effect is weak for more distant helices, a competition between the SC element formation and the optimal dipole-dipole interaction of alpha-helices is proposed as a mechanism for tertiary structure formation in 4 helix bundle proteins. The SC-forming potential of different arrangements as well as the pitfalls of the SC definition are also discussed.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:Proteins. - 48 : 2 (2002), p. 320-326. -
További szerzők:Simon István
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5.

001-es BibID:BIBFORM031396
035-os BibID:PMID:15971204 WOS:000230778100016
Első szerző:Fuxreiter Mónika (kutató vegyész)
Cím:Flexibility of prolyl oligopeptidase : molecular dynamics and molecular framework analysis of the potential substrate pathways / Monika Fuxreiter, Csaba Magyar, Tünde Juhász, Zoltán Szeltner, László Polgár, István Simon
Dátum:2005
Megjegyzések:The flexibility of prolyl oligopeptidase has been investigated using molecular dynamics (MD) and molecular framework approaches to delineate the route of the substrate to the active site. The selectivity of the enzyme is mediated by a seven-bladed beta-propeller that in the crystal structure does not indicate the possible passage for the substrate to the catalytic center. Its open topology however, could allow the blades to move apart and let the substrate into the large central cavity. Flexibility analysis of prolyl oligopeptidase structure using the FIRST (Floppy Inclusion and Rigid Substructure Topology) approach and the atomic fluctuations derived from MD simulations demonstrated the rigidity of the propeller domain, which does not permit the substrate to approach the active site through this domain. Instead, a smaller tunnel at the inter-domain region comprising the highly flexible N-terminal segment of the peptidase domain and a facing hydrophilic loop from the propeller (residues 192-205) was identified by cross-correlation analysis and essential dynamics as the only potential pathway for the substrate. The functional importance of the flexible loop has been also verified by kinetic analysis of the enzyme with a split loop. Catalytic effect of engineered disulfide bridges was rationalized by characterizing the concerted motions of the two domains.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:Proteins. - 60 : 3 (2005), p. 504-512. -
További szerzők:Magyar Csaba Juhász Tünde Szeltner Zoltán Polgár László Simon István
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6.

001-es BibID:BIBFORM049596
Első szerző:Lábas Anikó
Cím:Optimization of reorganization energy drives evolution of the designed Kemp eliminase KE07 / A. Labas, E. Szabo, L. Mones, M. Fuxreiter
Dátum:2013
ISSN:1570-9639
Megjegyzések:Understanding enzymatic evolution is essential to engineer enzymes with improved activities or to generate enzymes with tailor-made activities. The computationally designed Kemp eliminase KE07 carries out an unnatural reaction by converting of 5-nitrobenzisoxazole to cyanophenol, but its catalytic efficiency is significantly lower than those of natural enzymes. Three series of designed Kemp eliminases (KE07, KE70, KE59) were shown to be evolvable with considerable improvement in catalytic efficiency. Here we use the KE07 enzyme as a model system to reveal those forces, which govern enzymatic evolution and elucidate the key factors for improving activity. We applied the Empirical Valence Bond (EVB) method to construct the free energy pathway of the reaction in the original KE07 design and the evolved R7 1/3H variant. We analyzed catalytic effect of residues and demonstrated that not all mutations in evolution are favorable for activity. In contrast to the small decrease in the activation barrier, in vitro evolution significantly reduced the reorganization energy. We developed an algorithm to evaluate group contributions to the reorganization energy and used this approach to screen for KE07 variants with potential for improvement. We aimed to identify those mutations that facilitate enzymatic evolution, but might not directly increase catalytic efficiency. Computational results in accord with experimental data show that all mutations, which appear during in vitro evolution were either neutral or favorable for the reorganization energy. These results underscore that distant mutations can also play role in optimizing efficiency via their contribution to the reorganization energy. Exploiting this principle could be a promising strategy for computer-aided enzyme design. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Biochimica et Biophysica Acta (BBA). Proteins and Proteomics. - 1834 : 5 (2013), p. 908-917. -
További szerzők:Szabó E. Mones, Letif Fuxreiter Mónika (1969-) (kutató vegyész)
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7.

001-es BibID:BIBFORM031400
035-os BibID:PMID:12112696
Első szerző:Mehler, E. L.
Cím:The role of hydrophobic microenvironments in modulating pKa shifts in proteins / E. L. Mehler, M. Fuxreiter, I. Simon, B. Garcia-Moreno E.
Dátum:2002
ISSN:0887-3585
Megjegyzések:The screened Coulomb potential (SCP) method, combined with a quantitative description of the microenvironments around titratable groups, based on the Hydrophobic Fragmental Constants developed by Rekker, has been applied to calculate the pK(a) values of groups embedded in extremely hydrophobic microenvironments in proteins. This type of microenvironment is not common; but constitutes a small class, where the protein's architecture has evolved to lend special properties to the embedded residue. They are of significant interest because they are frequently important in catalysis and in proton and electron transfer reactions. In the SCP treatment these special cases are treated locally and therefore do not affect the accuracy of the pK(a) values calculated for other residues in less hydrophobic environments. Here the calibration of the algorithm is extended with the help of earlier results from lysozyme and of three mutants of staphylococcal nuclease (SNase) that were specially designed to measure the energetics of ionization of titratable groups buried in extremely hydrophobic microenvironments. The calibrated algorithm was subsequently applied to a fourth mutant of SNase and then to a very large dimeric amine oxidase of 1284 residues, where 334 are titratable. The observed pK(a) shifts of the buried residues are large (up to 4.7 pK units), and all cases are well reproduced by the calculations with a root mean square error of 0.22. These results support the hypothesis that protein electrostatics can only be described correctly and self-consistently if the inherent heterogeneity of these systems is properly accounted for.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
külföldön készült közlemény
Megjelenés:Proteins. - 48 : 2 (2002), p. 283-292. -
További szerzők:Fuxreiter Mónika (1969-) (kutató vegyész) Simon István B. Garcia-Moreno, E.
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8.

001-es BibID:BIBFORM031405
035-os BibID:WOS:000239103800017 PMID:16761278
Első szerző:Solt Iván
Cím:Phosphorylation-induced transient intrinsic structure in the kinase-inducible domain of CREB facilitates its recognition by the KIX domain of CBP / Iván Solt, Csaba Magyar, István Simon, Peter Tompa, Monika Fuxreiter
Dátum:2006
ISSN:0887-3585
Megjegyzések:Phosphorylation at Ser-133 of the kinase inducible domain of CREB (KID) triggers its binding to the KIX domain of CBP via a concomitant coil-to-helix transition. The exact role of this key event is still puzzling: it does not switch between disordered and ordered states, nor its direct interactions fully account for selectivity. Hence, we reasoned that phosphorylation may shift the conformational preferences of KID towards a binding-competent state. To this end we investigated the intrinsic structural properties of the unbound KID in phosphorylated and unphosphorylated forms by simulated annealing and molecular dynamics simulations. Although helical populations show subtle differences, phosphorylation reduces the flexibility of the turn segment connecting the two helices in the complexed structure and induces a transient structural element that corresponds to its bound conformation. It is stabilized by the pSer-133-Arg-131 interaction, which is absent from the unphosphorylated KID. Diminishing this coupling decreases the 3.1 kcal/mol contribution of pSer-133 to the binding free energy (Delta G(bind)) of the phosphorylated KID to KIX by 1.1 kcal/mol, as computed in reference to Ser-133. In a binding competent form of the S133E KID mutant, the contribution of Glu-133 to Delta G(bind) is by 1.5 kcal/mol smaller than that of pSer, suggesting that altered structural properties due to pSer -> Glu replacement impair the binding affinity. Thus, we propose that phoshorylation contributes to selectivity not merely by the direct interactions of the phosphate group with KIX, but also by promoting the formation of a transient structural element in the highly conserved turn segment.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:Proteins. - 64 : 3 (2006), p. 749-757. -
További szerzők:Magyar Csaba Simon István Tompa Péter Fuxreiter Mónika (1969-) (kutató vegyész)
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9.

001-es BibID:BIBFORM082447
Első szerző:Tüű-Szabó Boldizsár
Cím:Altered dynamics may drift pathological fibrillization in membraneless organelles / B. Tüű-Szabó, G. Hoffka, N. Duro, M. Fuxreiter
Dátum:2019
ISSN:1570-9639
Megjegyzések:Protein phase transition can generate non-membrane bound cellular compartments, which can convert from liquid-like to solid-like states. While the molecular driving forces of phase separation have been largely understood, much less is known about the mechanisms of material-state conversion. We apply a recently developed algorithm to describe the weak interaction network of multivalent motifs, and simulate the effect of pathological mutations. We demonstrate that linker dynamics is critical to the material-state of biomolecular condensates. We show that linker flexibility/mobility is a major regulator of the weak, heterogeneous meshwork of multivalent motifs, which promotes phase transition and maintains a liquid-like state. Decreasing linker dynamics increases the propensity of amyloid-like fragments via hampering the motif-exchange and reorganization of the weak interaction network. In contrast, increasing linker mobility may compensate rigidifying mutations, suggesting that the meshwork of weak, variable interactions may provide a rescue mechanism from aggregation. Motif affinity, on the other hand, has a moderate impact on fibrillization. Here we demonstrate that the fuzzy framework provides an efficient approach to handle the intricate organization of membraneless organelles, and could also be applicable to screen for pathological effects of mutations.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Matematikai és természettudományok - Kémiai tudományok
Megjelenés:Biochimica et Biophysica Acta (BBA). Proteins and Proteomics. - 1867 : 10 (2019), p. 988-998. -
További szerzők:Hoffka Gyula (1992-) (vegyész) Duró Norbert (1990-) (biotechnológus) Fuxreiter Mónika (1969-) (kutató vegyész)
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