TY - JOUR AU - Horváth, Dániel AU - Stráner, Pál AU - Taricska, Nóra AU - Fazekas, Zsolt AU - Karancsiné Menyhárd, Dóra AU - Perczel, András TI - Influence of Trp-Cage on the Function and Stability of GLP-1R Agonist Exenatide Derivatives JF - JOURNAL OF MEDICINAL CHEMISTRY J2 - J MED CHEM PY - 2024 SN - 0022-2623 DO - 10.1021/acs.jmedchem.4c01553 UR - https://m2.mtmt.hu/api/publication/35262191 ID - 35262191 LA - English DB - MTMT ER - TY - JOUR AU - Dürvanger, Zsolt AU - Bencs, Fruzsina AU - Karancsiné Menyhárd, Dóra AU - Horváth, Dániel AU - Perczel, András TI - Solvent induced amyloid polymorphism and the uncovering of the elusive class 3 amyloid topology JF - COMMUNICATIONS BIOLOGY J2 - COMMUN BIOL VL - 7 PY - 2024 IS - 1 SN - 2399-3642 DO - 10.1038/s42003-024-06621-8 UR - https://m2.mtmt.hu/api/publication/35166269 ID - 35166269 AB - Aggregation-prone-motifs (APRs) of proteins are short segments, which – as isolated peptides - form diverse amyloid-like crystals. We introduce two APRs - designed variants of the incretin mimetic Exendin-4 - that both display crystal-phase polymorphism. Crystallographic and spectroscopic analysis revealed that a single amino-acid substitution can greatly reduce topological variability: while LYIQWL can form both parallel and anti-parallel β-sheets, LYIQNL selects only the former. We also found that the parallel/anti-parallel switch of LYIQWL can be induced by simply changing the crystallization temperature. One crystal form of LYIQNL was found to belong to the class 3 topology, an arrangement previously not encountered among proteinogenic systems. We also show that subtle environmental changes lead to crystalline assemblies with different topologies, but similar interfaces. Spectroscopic measurements showed that polymorphism is already apparent in the solution state. Our results suggest that the temperature-, sequence- and environmental sensitivity of physiological amyloids is reflected in assemblies of the APR segments, which, complete with the new class 3 crystal form, effectively sample all the originally proposed basic topologies of amyloid-like aggregates. LA - English DB - MTMT ER - TY - JOUR AU - Fazekas, Zsolt AU - Karancsiné Menyhárd, Dóra AU - Perczel, András TI - LoCoHD: a metric for comparing local environments of proteins JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 15 PY - 2024 IS - 1 SN - 2041-1723 DO - 10.1038/s41467-024-48225-0 UR - https://m2.mtmt.hu/api/publication/34851953 ID - 34851953 AB - Protein folds and the local environments they create can be compared using a variety of differently designed measures, such as the root mean squared deviation, the global distance test, the template modeling score or the local distance difference test. Although these measures have proven to be useful for a variety of tasks, each fails to fully incorporate the valuable chemical information inherent to atoms and residues, and considers these only partially and indirectly. Here, we develop the highly flexible local composition Hellinger distance (LoCoHD) metric, which is based on the chemical composition of local residue environments. Using LoCoHD, we analyze the chemical heterogeneity of amino acid environments and identify valines having the most conserved-, and arginines having the most variable chemical environments. We use LoCoHD to investigate structural ensembles, to evaluate critical assessment of structure prediction (CASP) competitors, to compare the results with the local distance difference test (lDDT) scoring system, and to evaluate a molecular dynamics simulation. We show that LoCoHD measurements provide unique information about protein structures that is distinct from, for example, those derived using the alignment-based RMSD metric, or the similarly distance matrix-based but alignment-free lDDT metric. LA - English DB - MTMT ER - TY - JOUR AU - Horváth, Dániel AU - Dürvanger, Zsolt AU - Karancsiné Menyhárd, Dóra AU - Sulyok-Eiler, Máté AU - Bencs, Fruzsina AU - Gyulai, Gergő AU - Horváth, Péter AU - Taricska, Nóra AU - Perczel, András TI - Polymorphic amyloid nanostructures of hormone peptides involved in glucose homeostasis display reversible amyloid formation JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 14 PY - 2023 IS - 1 PG - 15 SN - 2041-1723 DO - 10.1038/s41467-023-40294-x UR - https://m2.mtmt.hu/api/publication/34084209 ID - 34084209 N1 - ELKH-ELTE Protein Modeling Research Group ELTE Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, H-1117, Hungary Laboratory of Structural Chemistry and Biology ELTE Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, H-1117, Hungary Hevesy György PhD School of Chemistry, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, H-1117, Hungary Laboratory of Interfaces and Nanostructures, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, H-1117, Hungary Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre utca 9, Budapest, 1092, Hungary Export Date: 2 October 2023 Correspondence Address: Perczel, A.; ELKH-ELTE Protein Modeling Research Group ELTE Eötvös Loránd University, Pázmány Péter sétány 1/A, Hungary; email: perczel.andras@ttk.elte.hu AB - A large group of hormones are stored as amyloid fibrils in acidic secretion vesicles before they are released into the bloodstream and readopt their functional state. Here, we identify an evolutionarily conserved hexapeptide sequence as the major aggregation-prone region (APR) of gastrointestinal peptides of the glucagon family: xFxxWL. We determine nine polymorphic crystal structures of the APR segments of glucagon-like peptides 1 and 2, and exendin and its derivatives. We follow amyloid formation by CD, FTIR, ThT assays, and AFM. We propose that the pH-dependent changes of the protonation states of glutamate/aspartate residues of APRs initiate switching between the amyloid and the folded, monomeric forms of the hormones. We find that pH sensitivity diminishes in the absence of acidic gatekeepers and amyloid formation progresses over a broad pH range. Our results highlight the dual role of short aggregation core motifs in reversible amyloid formation and receptor binding. LA - English DB - MTMT ER - TY - JOUR AU - Gadanecz, Márton AU - Fazekas, Zsolt AU - Pálfy, Gyula AU - Karancsiné Menyhárd, Dóra AU - Perczel, András TI - NMR-Chemical-Shift-Driven Protocol Reveals the Cofactor-Bound, Complete Structure of Dynamic Intermediates of the Catalytic Cycle of Oncogenic KRAS G12C Protein and the Significance of the Mg2+ Ion JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 15 SN - 1661-6596 DO - 10.3390/ijms241512101 UR - https://m2.mtmt.hu/api/publication/34081394 ID - 34081394 N1 - Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter stny. 1/A, Budapest, H-1117, Hungary Hevesy György PhD School of Chemistry, Eötvös Loránd University, Pázmány Péter stny. 1/A, Budapest, H-1117, Hungary ELKH-ELTE Protein Modeling Research Group, Eötvös Loránd Research Network (ELKH), Pázmány Péter stny. 1/A, Budapest, H-1117, Hungary Department of Biology, Institute of Biochemistry, ETH Zürich, Zürich, 8093, Switzerland Cited By :1 Export Date: 5 July 2024 Correspondence Address: Perczel, A.; Laboratory of Structural Chemistry and Biology, Pázmány Péter stny. 1/A, Hungary; email: perczel.andras@ttk.elte.hu AB - In this work, catalytically significant states of the oncogenic G12C variant of KRAS, those of Mg2+-free and Mg2+-bound GDP-loaded forms, have been determined using CS-Rosetta software and NMR-data-driven molecular dynamics simulations. There are several Mg2+-bound G12C KRAS/GDP structures deposited in the Protein Data Bank (PDB), so this system was used as a reference, while the structure of the Mg2+-free but GDP-bound state of the RAS cycle has not been determined previously. Due to the high flexibility of the Switch-I and Switch-II regions, which also happen to be the catalytically most significant segments, only chemical shift information could be collected for the most important regions of both systems. CS-Rosetta was used to derive an “NMR ensemble” based on the measured chemical shifts, which, however, did not contain the nonprotein components of the complex. We developed a torsional restraint set for backbone torsions based on the CS-Rosetta ensembles for MD simulations, overriding the force-field-based parametrization in the presence of the reinserted cofactors. This protocol (csdMD) resulted in complete models for both systems that also retained the structural features and heterogeneity defined by the measured chemical shifts and allowed a detailed comparison of the Mg2+-bound and Mg2+-free states of G12C KRAS/GDP. LA - English DB - MTMT ER - TY - JOUR AU - Nagy-Fazekas, Dóra AU - Fazekas, Zsolt AU - Taricska, Nóra AU - Stráner, Pál AU - Karancsiné Menyhárd, Dóra AU - Perczel, András TI - Inhibitor Design Strategy for Myostatin: Dynamics and Interaction Networks Define the Affinity and Release Mechanisms of the Inhibited Complexes JF - MOLECULES J2 - MOLECULES VL - 28 PY - 2023 IS - 15 SN - 1420-3049 DO - 10.3390/molecules28155655 UR - https://m2.mtmt.hu/api/publication/34078730 ID - 34078730 N1 - Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, H-1117, Hungary Hevesy György PhD School of Chemistry, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, H-1117, Hungary ELKH-ELTE Protein Modeling Research Group, Eötvös Loránd Research Network (ELKH), Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, H-1117, Hungary Export Date: 2 October 2023 CODEN: MOLEF Correspondence Address: Karancsiné Menyhárd, D.; Laboratory of Structural Chemistry and Biology, Pázmány Péter sétány 1/A, Pázmány Péter sétány 1/A, Hungary; email: dora.k.menyhard@ttk.elte.hu Correspondence Address: Perczel, A.; Laboratory of Structural Chemistry and Biology, Pázmány Péter sétány 1/A, Hungary; email: perczel.andras@ttk.elte.hu AB - Myostatin, an important negative regulator of muscle mass, is a therapeutic target for muscle atrophic disorders such as muscular dystrophy. Thus, the inhibition of myostatin presents a strategy to treat these disorders. It has long been established that the myostatin prodomain is a strong inhibitor of the mature myostatin, and the minimum peptide of the prodomain—corresponding to the α1-helix of its lasso-region—responsible for the inhibitory efficiency was defined and characterized as well. Here we show that the minimum peptide segment based on the growth differentiation factor 11 (GDF11), which we found to be more helical in its stand-alone solvated stfate than the similar segment of myostatin, is a promising new base scaffold for inhibitor design. The proposed inhibitory peptides in their solvated state and in complex with the mature myostatin were analyzed by in silico molecule modeling supplemented with the electronic circular dichroism spectroscopy measurements. We defined the Gaussian–Mahalanobis mean score to measure the fraction of dihedral angle-pairs close to the desired helical region of the Ramachandran-plot, carried out RING analysis of the peptide-protein interaction networks and characterized the internal motions of the complexes using our rigid-body segmentation protocol. We identified a variant—11m2—that is sufficiently ordered both in solvent and within the inhibitory complex, forms a high number of contacts with the binding-pocket and induces such changes in its internal dynamics that lead to a rigidified, permanently locked conformation that traps this peptide in the binding site. We also showed that the naturally evolved α1-helix has been optimized to simultaneously fulfill two very different roles: to function as a strong binder as well as a good leaving group. It forms an outstanding number of non-covalent interactions with the mature core of myostatin and maintains the most ordered conformation within the complex, while it induces independent movement of the gate-keeper β-hairpin segment assisting the dissociation and also results in the least-ordered solvated form which provides extra stability for the dissociated state and discourages rebinding. LA - English DB - MTMT ER - TY - JOUR AU - Antal, Violetta AU - Schay, Gusztav AU - Kétszeri, Máté Csaba AU - Ungvari-Veres, Anita AU - Paszty, Katalin AU - Kellermayer, Miklos AU - Karancsiné Menyhárd, Dóra AU - Tory, Kálmán TI - The regulation of the nephrin-nephrin distance by podocin mediates the interallelic interactions of the NPHS2 R229Q variant JF - PEDIATRIC NEPHROLOGY J2 - PEDIATR NEPHROL VL - 38 PY - 2023 IS - 7 SP - 2262 EP - 2263 PG - 2 SN - 0931-041X UR - https://m2.mtmt.hu/api/publication/34064337 ID - 34064337 LA - English DB - MTMT ER - TY - JOUR AU - Kiss-Szemán, Anna Júlia AU - Takács, Luca AU - Orgován, Zoltán AU - Stráner, Pál AU - Jákli, Imre AU - Schlosser, Gitta (Vácziné) AU - Masiulis, Simonas AU - Harmat, Veronika AU - Karancsiné Menyhárd, Dóra AU - Perczel, András TI - A carbapenem antibiotic inhibiting a mammalian serine protease: structure of the acylaminoacyl peptidase–meropenem complex JF - CHEMICAL SCIENCE J2 - CHEM SCI VL - 13 PY - 2022 IS - 48 SP - 14264 EP - 14276 PG - 13 SN - 2041-6520 DO - 10.1039/D2SC05520A UR - https://m2.mtmt.hu/api/publication/33307131 ID - 33307131 N1 - Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, Hungary Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary ELKH-ELTE Protein Modelling Research Group, Eötvös Loránd Research Network, Budapest, Hungary ELKH-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary Materials and Structural Analysis Division, Thermo Fisher Scientific, Eindhoven, Netherlands Export Date: 28 March 2023 CODEN: CSHCC Correspondence Address: Harmat, V.; Laboratory of Structural Chemistry and Biology, Pázmány Péter sétány 1/A, Hungary; email: veronika.harmat@ttk.elte.hu Correspondence Address: Menyhárd, D.K.; Laboratory of Structural Chemistry and Biology, Pázmány Péter sétány 1/A, Hungary; email: dora.k.menyhard@ttk.elte.hu Correspondence Address: Perczel, A.; Laboratory of Structural Chemistry and Biology, Pázmány Péter sétány 1/A, Hungary; email: perczel.andras@ttk.elte.hu AB - The structure of porcine AAP (pAAP) in a covalently bound complex with meropenem was determined by cryo-EM to 2.1 Å resolution, showing the mammalian serine-protease inhibited by a carbapenem antibiotic. LA - English DB - MTMT ER - TY - CONF AU - Antal, Violetta AU - Schay, Gusztáv AU - Kétszeri, Máté Csaba AU - Ungvári-Veres, Anita AU - Pászty, Katalin AU - Kellermayer, Miklós AU - Karancsiné Menyhárd, Dóra AU - Tory, Kálmán TI - Oly távol vagy tőlem, és mégis közel: patogén podocintársulások nefrin-nefrin távolságra gyakorolt hatása T2 - Magyar Gyermeknephrológiai Egyesület 2022. évi Kongresszusa PY - 2022 SP - 22 EP - 23 PG - 2 UR - https://m2.mtmt.hu/api/publication/33138397 ID - 33138397 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Fazekas, Zsolt AU - Karancsiné Menyhárd, Dóra AU - Perczel, András TI - Omicron Binding Mode: Contact Analysis and Dynamics of the Omicron Receptor-Binding Domain in Complex with ACE2 JF - JOURNAL OF CHEMICAL INFORMATION AND MODELING J2 - J CHEM INF MODEL VL - 62 PY - 2022 IS - 16 SP - 3844 EP - 3853 PG - 10 SN - 1549-9596 DO - 10.1021/acs.jcim.2c00397 UR - https://m2.mtmt.hu/api/publication/33040605 ID - 33040605 AB - On 26 November 2021, the WHO classified the Omicron variant of the SARS-CoV-2 virus (B.1.1.529 lineage) as a Health, 2022). The Omicron variant contains as many as 26 unique mutations of effects not yet determined (Venkatakrishnan, A., Open Science Framework, 2021). Out of its total of 34 Spike protein mutations, 15 are located on the receptor-binding domain (Sthat directly contacts the angiotensin-converting enzyme 2 (ACE2) host receptor and is also a primary target for antibodies. Here, we studied the binding mode of the S-RBD domain of the Spike protein carrying the Omicron mutations and the globular domain of human ACE2 using molecular dynamics (MD) simulations. We identified new and key Omicron-specific interactions such as R-493 (of mutation Q493R), which forms salt bridges both with E(35 )and D(38 )of ACE2, Y-501 (N501Y), which forms an edge-to-face aromatic interaction with Y-41, and Y-505 (Y505H), which makes an H-bond with E-37 and K-353. The glycan chains of ACE2 also bind differently in the WT and Omicron variants in response to different charge distributions on the surface of Spike proteins. However, while the Omicron mutations considerably improve the overall electrostatic fit of the two interfaces, the total number of specific and favorable interactions between the two does not increase. The dynamics of the complexes are highly affected too, making the Omicron S-RBD:ACE2 complex more rigid; the two main interaction sites, Patches I and II, isolated in the WT complex, become connected in the Omicron complex through the alternating interaction of R-493 and R(498 )with E(35 )and D-38. LA - English DB - MTMT ER -