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Helix stabilization

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https://www.readbyqxmd.com/read/28922503/modulating-the-structural-properties-of-alpha-gamma-hybrid-peptides-by-alpha-amino-acid-residues-uniform-12-helix-versus-mixed-12-10-helix
#1
Rajkumar Misra, K Muruga Poopathi Raja, Hans-Jörg Hofmann, Hosahudya Gopi
The most important natural a- and 310-helices are stabilized by unidirectional intramolecular hydrogen bonds along the helical cylinder. In contrast, we are reporting here on 12/10-helical conformations with alternately changing H-bond directionality in sequences of alpha,gamma-hybrid peptides [P1: Boc-Ala-Aic-Ala-Aic-COOH; P2: Boc-Leu-Aic-Leu-Aic-OEt; P3: Boc-Leu-Aic-Leu-Aic-Leu-Aic-Aib-OMe; P4: Boc-Ala-Aic-Ala-Aic-Ala-Aic-Ala-OMe; P5: Boc-Leu-Aic-Leu-Aic-Leu-Aic-Leu-Aic-Aib-OMe] composed of natural a-amino acids and the achiral gamma4,4-dimethyl substituted g-amino acid Aic in solution and in single crystals...
September 18, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28921993/lactam-stapled-cell-penetrating-peptides-cell-uptake-and-membrane-binding-properties
#2
Marco J Klein, Samuel Schmidt, Parvesh Wadhwani, Jochen Bürck, Johannes Reichert, Sergii Afonin, Marina Berditsch, Tim Schober, Roland Brock, Manfred Kansy, Anne S Ulrich
Stapling of side chains to stabilize an α-helical structure has been generally associated with an increased uptake of CPPs. Here, we compare 4 amphiphilic stapled peptides with their linear counterparts in terms of their membrane binding and conformational features, in order to correlate these with uptake efficiency and toxicological effects. The impact of lactam stapling was found to vary strongly with regard to the different aspects of peptide-membrane interactions. Nearly all stapled peptides caused less membrane perturbation (vesicle leakage, hemolysis, bacterial lysis) than their linear counterparts...
September 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28918491/dynamics-of-allosteric-modulation-of%C3%A2-lymphocyte-function-associated-antigen-1-closure-open-switch-unveiling-the-structural-mechanisms-associated-with-outside-in-signaling-activation
#3
Maryam Abdullahi, Fisayo A Olotu, Mahmoud E Soliman
OBJECTIVES: To provide insight into the dynamics of the shape-shifting mechanistic events associated with the opening (activation) of Lymphocyte Function Associated Antigen-1 upon allosteric modulation by an activator, ICAM Binding Enhancer-667 (IBE-667), using molecular dynamics simulation. RESULTS: Various parameters were used to appropriately describe and understand the sequence of events that characterized its activation across the simulation period such as residual distances, TriCα angles; as well as the dihedral angle...
September 16, 2017: Biotechnology Letters
https://www.readbyqxmd.com/read/28917403/cataract-surgery-in-patients-with-late-onset-retinal-degeneration
#4
Vasileios T Papastavrou, Shyamanga Borooah, Jill M O'Brien, Neeta Ray-Chaudhuri, Baljean Dhillon, Rute V Vieira, Andrew C Browning
PURPOSE: To review the outcomes in a series of patients with long anterior lens zonular fibers associated with late-onset retinal degeneration who had phacoemulsification cataract surgery. SETTING: Newcastle Eye Centre, Newcastle upon Tyne, United Kingdom. DESIGN: Retrospective case series. METHODS: Inclusion criteria were patients with genetically confirmed late-onset retinal degeneration requiring cataract surgery...
August 2017: Journal of Cataract and Refractive Surgery
https://www.readbyqxmd.com/read/28917050/preparation-of-selenocysteine-containing-forms-of-human-selenok-and-selenos
#5
Zhengqi Zhang, Jun Liu, Sharon Rozovsky
Selenoprotein K (SELENOK) and Selenoprotein S (SELENOS) are the members of the endoplasmic-reticulum-associated degradation (ERAD) complex, which is responsible for translocating misfolded proteins from the endoplasmic reticulum (ER) to the cytosol for degradation. Besides its involvement in the ERAD, SELENOK was shown to bind and stabilize the palmitoyl transferase DHHC6, and thus contributes to palmitoylation. SELENOK and SELENOS reside in the ER membrane by the way of a single transmembrane helix. Both contain an intrinsically disordered region with a selenocysteine (Sec) located one or two residues away from the C-terminus...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28911198/loss-of-native-%C3%AE-synuclein-multimerization-by-strategically-mutating-its-amphipathic-helix-causes-abnormal-vesicle-interactions-in-neuronal-cells
#6
Ulf Dettmer, Nagendran Ramalingam, Victoria E von Saucken, Tae-Eun Kim, Andrew J Newman, Elizabeth Terry-Kantor, Silke Nuber, Maria Ericsson, Saranna Fanning, Tim Bartels, Susan Lindquist, Oren A Levy, Dennis Selkoe
α-Synuclein (αS) forms round cytoplasmic inclusions in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence suggests a physiological function of αS in vesicle trafficking and release. In contrast to earlier tenets, recent work indicates that αS normally exists in cells in a dynamic equilibrium between monomers and tetramers/multimers. We engineered αS mutants incapable of multimerization, leading to excess monomers at vesicle membranes. By EM, such mutants induced prominent vesicle clustering, leading to round cytoplasmic inclusions...
September 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28900796/structural-rationale-for-the-cross-resistance-of-tumor-cells-bearing-the-a399v-variant-of-elongation-factor-eef1a1-to-the-structurally-unrelated-didemnin-b-ternatin-nannocystin-a-and-ansatrienin-b
#7
Pedro A Sánchez-Murcia, Álvaro Cortés-Cabrera, Federico Gago
At least four classes of structurally distinct natural products with potent antiproliferative activities target the translation elongation factor eEF1A1, which is best known as the G-protein that delivers amino acyl transfer RNAs (aa-tRNAs) to ribosomes during mRNA translation. We present molecular models in atomic detail that provide a common structural basis for the high-affinity binding of didemnin B, ternatin, ansatrienin B and nannocystin A to eEF1A1, as well as a rationale based on molecular dynamics results that accounts for the deleterious effect of replacing alanine 399 with valine...
September 12, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28900197/structural-insights-into-the-middle-east-respiratory-syndrome-coronavirus-4a-protein-and-its-dsrna-binding-mechanism
#8
Maria Batool, Masaud Shah, Mahesh Chandra Patra, Dhanusha Yesudhas, Sangdun Choi
Middle East respiratory syndrome coronavirus (MERS-CoV) has evolved to navigate through the sophisticated network of a host's immune system. The immune evasion mechanism including type 1 interferon and protein kinase R-mediated antiviral stress responses has been recently attributed to the involvement of MERS-CoV protein 4a (p4a) that masks the viral dsRNA. However, the structural mechanism of how p4a recognizes and establishes contacts with dsRNA is not well explained. In this study, we report a dynamic mechanism deployed by p4a to engage the viral dsRNA and make it unavailable to the host immune system...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28899488/investigating-the-structural-and-functional-features-of-representative-recombinants-of-chondroitinase-abc-i
#9
Khadijeh Moradi, Seyedeh Akram Shirdel, Masoumeh Shamsi, Vahab Jafarian, Khosrow Khalifeh
Chondroitin Sulfate Proteoglycans (CSPGs) are the main inhibitors for axon regeneration after damaging of Central Nervous System (CNS). Chondroitinase ABC I (cABC I) can degrade CSPGs by removing chondroitin and dermatan sulfate side chains from proteoglycans. Hence, it may be considered as an attractive candidate in biomedicine. For practical applications of this enzyme, increasing the effective circulating level and reducing the number and volume of injections for patients is one of the main concerns which is directly related to conformational stability and catalytic efficiency of the enzyme...
December 2017: Enzyme and Microbial Technology
https://www.readbyqxmd.com/read/28898928/importance-of-the-second-extracellular-loop-for-melatonin-mt1-receptor-function-and-absence-of-melatonin-binding-in-gpr50
#10
Nathalie Clement, Nicolas Renault, Jean-Luc Guillaume, Erika Cecon, Anne-Sophie Journé, Xavier Laurent, Kenjiro Tadagaki, Francis Cogé, Arnaud Gohier, Philippe Delagrange, Philippe Chavatte, Ralf Jockers
BACKGROUND AND PURPOSE: Recent crystal structures of G protein-coupled receptors (GPCRs) highlight the previously unappreciated role of the 2(nd) extracellular (E2) loop in ligand binding and gating and receptor activation. Here we studied the role of the E2 loop in the activation of the melatonin MT1 receptor (MT1 ) and in the inactivation of the closely related orphan GPR50 receptor. EXPERIMENTAL APPROACH: Chimeric MT1 -GPR50 receptors were generated and analyzed for 2-[(125) I]iodomelatonin binding, Gi /cAMP signaling and β-arrestin 2 recruitment assisted by computational molecular dynamics (MD) simulations...
September 12, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28898430/effect-of-drying-methods-on-the-structure-thermo-and-functional-properties-of-fenugreek-trigonella-foenuem-graecum-protein-isolate
#11
Samira Feyzi, Mehdi Varidi, Fatemeh Zare, Mohammad Javad Varidi
BACKGROUND: Different drying methods due to protein denaturation could alter proteins' functional properties, as well as structure. So, this study focused on the effect of different drying methods on amino acid content, thermo and functional properties, and protein structure of fenugreek protein isolate. RESULTS: Freeze and spray drying methods resulted in comparable protein solubility, dynamic surface and interfacial tensions, foaming and emulsifying properties except for emulsion stability...
September 12, 2017: Journal of the Science of Food and Agriculture
https://www.readbyqxmd.com/read/28895717/backbone-circularization-coupled-with-optimization-of-connecting-segment-in-effectively-improving-the-stability-of-granulocyte-colony-stimulating-factor
#12
Takamitsu Miyafusa, Risa Shibuya, Wataru Nishima, Rie Ohara, Chuya Yoshida, Shinya Honda
Backbone circularization of protein is a powerful method to improve its structural stability. In this paper, we presumed that a tight connection leads to much higher stability. Therefore, we designed circularized variants of a granulocyte-colony stimulating factor (G-CSF) with a structurally optimized terminal connection. To estimate the appropriate length of the connection, we surveyed the Protein Data Bank to find local structures as a model for the connecting segment. We set the library of local structures composed of "helix-loop-helix," subsequently selected entries similar to the G-CSF terminus, and finally sorted the hit structures according to the loop length...
September 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28894181/rigidly-connected-multispecific-artificial-binders-with-adjustable-geometries
#13
Yufan Wu, Alexander Batyuk, Annemarie Honegger, Fabian Brandl, Peer R E Mittl, Andreas Plückthun
Multivalent binding proteins can gain biological activities beyond what is inherent in the individual binders, by bringing together different target molecules, restricting their conformational flexibility or changing their subcellular localization. In this study, we demonstrate a method to build up rigid multivalent and multispecific scaffolds by exploiting the modular nature of a repeat protein scaffold and avoiding flexible linkers. We use DARPins (Designed Ankyrin Repeat Proteins), synthetic binding proteins based on the Ankyrin-repeat protein scaffold, as binding units...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28891286/conformation-preservation-of-alpha-helical-peptides-within-supramolecular-filamentous-assemblies
#14
Yi Li, Yuzhu Wang, Shih-Hao Ou, Lye Lin Lock, Xuankuo Xu, Sanchayita Ghose, Zheng Jian Li, Honggang Cui
Hydrogen-bonded β-sheets are the most commonly explored building motifs for creating peptide-based filamentous nanostructures, however, most bioactive epitopes must assume an α-helix conformation to exert their functions. Incorporating α-helical sequences into β-sheet-forming peptides often involves the use of a flexible spacer to alleviate the steric impact of the intermolecular hydrogen bonding on the α-helical conformation. In this context, we report our findings on the alkylation-regulated conformation preservation of α-helical peptides within their filamentous assemblies...
September 11, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/28887512/lna-effects-on-dna-binding-and-conformation-from-single-strand-to-duplex-and-triplex-structures
#15
Y Vladimir Pabon-Martinez, You Xu, Alessandra Villa, Karin E Lundin, Sylvain Geny, Chi-Hung Nguyen, Erik B Pedersen, Per T Jørgensen, Jesper Wengel, Lennart Nilsson, C I Edvard Smith, Rula Zain
The anti-gene strategy is based on sequence-specific recognition of double-strand DNA by triplex forming (TFOs) or DNA strand invading oligonucleotides to modulate gene expression. To be efficient, the oligonucleotides (ONs) should target DNA selectively, with high affinity. Here we combined hybridization analysis and electrophoretic mobility shift assay with molecular dynamics (MD) simulations to better understand the underlying structural features of modified ONs in stabilizing duplex- and triplex structures...
September 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28886645/a-multi-state-coarse-grained-modeling-approach-for-an-intrinsically-disordered-peptide
#16
Farhad Ramezanghorbani, Cahit Dalgicdir, Mehmet Sayar
Many proteins display a marginally stable tertiary structure, which can be altered via external stimuli. Since a majority of coarse grained (CG) models are aimed at structure prediction, their success for an intrinsically disordered peptide's conformational space with marginal stability and sensitivity to external stimuli cannot be taken for granted. In this study, by using the LKα14 peptide as a test system, we demonstrate a bottom-up approach for constructing a multi-state CG model, which can capture the conformational behavior of this peptide in three distinct environments with a unique set of interaction parameters...
September 7, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28885830/oligoprolines-as-molecular-entities-for-controlling-distance-in-biological-and-material-sciences
#17
Stefanie Dobitz, Matthew R Aronoff, Helma Wennemers
Nature utilizes large biomolecules to fulfill tasks that require spatially well-defined arrangements at the molecular level such as electron transfer, ligand-receptor interactions, or catalysis. The creation of synthetic molecules that enable precise control over spacing and functionalization provides opportunities across diverse disciplines. Key requirements of functionalizable oligomeric scaffolds include the specific control of their molecular properties where the correct balance of flexibility and rigidity must be maintained in addition to the prerequisite of defined length...
September 8, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28878762/the-c-terminal-six-amino-acids-of-the-fnt-channel-foca-are-required-for-formate-translocation-but-not-homopentamer-integrity
#18
Doreen Hunger, Marie Röcker, Dörte Falke, Hauke Lilie, R Gary Sawers
FocA is the archetype of the pentameric formate-nitrite transporter (FNT) superfamily of channels, members of which translocate small organic and inorganic anions across the cytoplasmic membrane of microorganisms. The N- and C-termini of each protomer are cytoplasmically oriented. A Y-L-R motif is found immediately after transmembrane helix 6 at the C-terminus of FNT proteins related to FocA, or those with a role in formate translocation. Previous in vivo studies had revealed that formate translocation through FocA was controlled by interaction with the formate-producing glycyl-radical enzyme pyruvate formate-lyase (PflB) or its structural and functional homolog, TdcE...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28876052/the-phe-ile-zipper-specific-interaction-motif-drives-antiparallel-coiled-coil-hexamer-formation
#19
Ryan K Spencer, Allon I Hochbaum
Coiled coils are a robust motif for exploring amino acid interactions, generating unique supramolecular structures, and expanding properties of biological based ma- terials. A recently discovered antiparallel coiled-coil hexamer (ACC-Hex, peptide 1) exhibits a unique interaction in which Phe and Ile residues from adjacent α-helices interact to form a Phe-Ile zipper within the hydrophobic core. Analysis of the X-ray crystallographic structure of ACC-Hex suggests that the stability of the six-helix bundle relies on specific interactions between the Phe and Ile residues...
September 6, 2017: Biochemistry
https://www.readbyqxmd.com/read/28874603/cancer-associated-arginine-to-histidine-mutations-confer-a-gain-in-ph-sensing-to-mutant-proteins
#20
Katharine A White, Diego Garrido Ruiz, Zachary A Szpiech, Nicolas B Strauli, Ryan D Hernandez, Matthew P Jacobson, Diane L Barber
The intracellular pH (pHi) of most cancers is constitutively higher than that of normal cells and enhances proliferation and cell survival. We found that increased pHi enabled the tumorigenic behaviors caused by somatic arginine-to-histidine mutations, which are frequent in cancer and confer pH sensing not seen with wild-type proteins. Experimentally raising the pHi increased the activity of R776H mutant epidermal growth factor receptor (EGFR-R776H), thereby increasing proliferation and causing transformation in fibroblasts...
September 5, 2017: Science Signaling
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