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  1. Article ; Online: Molecular Peptide Grafting as a Tool to Create Novel Protein Therapeutics.

    Komar, Anton A

    Molecules (Basel, Switzerland)

    2023  Volume 28, Issue 5

    Abstract: The study of peptides (synthetic or corresponding to discrete regions of proteins) has facilitated the understanding of protein structure-activity relationships. Short peptides can also be used as powerful therapeutic agents. However, the functional ... ...

    Abstract The study of peptides (synthetic or corresponding to discrete regions of proteins) has facilitated the understanding of protein structure-activity relationships. Short peptides can also be used as powerful therapeutic agents. However, the functional activity of many short peptides is usually substantially lower than that of their parental proteins. This is (as a rule) due to their diminished structural organization, stability, and solubility often leading to an enhanced propensity for aggregation. Several approaches have emerged to overcome these limitations, which are aimed at imposing structural constraints into the backbone and/or sidechains of the therapeutic peptides (such as molecular stapling, peptide backbone circularization and molecular grafting), therefore enforcing their biologically active conformation and thus improving their solubility, stability, and functional activity. This review provides a short summary of approaches aimed at enhancing the biological activity of short functional peptides with a particular focus on the peptide grafting approach, whereby a functional peptide is inserted into a scaffold molecule. Intra-backbone insertions of short therapeutic peptides into scaffold proteins have been shown to enhance their activity and render them a more stable and biologically active conformation.
    MeSH term(s) Peptides/chemistry ; Molecular Conformation ; Protein Conformation
    Chemical Substances Peptides
    Language English
    Publishing date 2023-03-05
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules28052383
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  2. Article ; Online: From Alpha to Beta - a co-translational way to fold?

    Komar, Anton A

    Cell cycle (Georgetown, Tex.)

    2022  Volume 21, Issue 16, Page(s) 1663–1666

    Abstract: Protein folding in the cell is largely a co-translational process occurring during protein synthesis on the ribosome. It has become evident that co-translational folding is characteristic to almost every protein in the cell of pro- and eukaryotic origin ... ...

    Abstract Protein folding in the cell is largely a co-translational process occurring during protein synthesis on the ribosome. It has become evident that co-translational folding is characteristic to almost every protein in the cell of pro- and eukaryotic origin that are single and multidomain, single and multisubunit, cytosolic, secretory and membrane. Co-translational protein folding begins very early during the process of polypeptide chain synthesis on the ribosome, with some secondary structure elements forming inside the ribosomal tunnel and some tertiary structures forming inside the vestibule (lower/wider) region of the ribosomal exit tunnel. However, many details of co-translational folding remains incompletely understood. New data show that folding of a β-barrel protein begins with formation of an α-helix inside the ribosome that rearranges into a β-hairpin structure as the growing peptide reaches the wider/vestibule region of the exit tunnel. While it was previously suggested that such scenario can take place on the ribosome, the new data provide the first experimental evidence in support of this notion.
    MeSH term(s) Peptides/chemistry ; Protein Biosynthesis ; Protein Folding ; Protein Structure, Secondary ; Ribosomes/metabolism
    Chemical Substances Peptides
    Language English
    Publishing date 2022-04-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.1080/15384101.2022.2062186
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    Zs.A 5881: Show issues Location:
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  3. Article ; Online: A Code Within a Code: How Codons Fine-Tune Protein Folding in the Cell.

    Komar, Anton A

    Biochemistry. Biokhimiia

    2021  Volume 86, Issue 8, Page(s) 976–991

    Abstract: The genetic code sets the correspondence between the sequence of a given nucleotide triplet in an mRNA molecule, called a codon, and the amino acid that is added to the growing polypeptide chain during protein synthesis. With four bases (A, G, U, and C), ...

    Abstract The genetic code sets the correspondence between the sequence of a given nucleotide triplet in an mRNA molecule, called a codon, and the amino acid that is added to the growing polypeptide chain during protein synthesis. With four bases (A, G, U, and C), there are 64 possible triplet codons: 61 sense codons (encoding amino acids) and 3 nonsense codons (so-called, stop codons that define termination of translation). In most organisms, there are 20 common/standard amino acids used in protein synthesis; thus, the genetic code is redundant with most amino acids (with the exception of Met and Trp) are being encoded by more than one (synonymous) codon. Synonymous codons were initially presumed to have entirely equivalent functions, however, the finding that synonymous codons are not present at equal frequencies in mRNA suggested that the specific codon choice might have functional implications beyond coding for amino acid. Observation of nonequivalent use of codons in mRNAs implied a possibility of the existence of auxiliary information in the genetic code. Indeed, it has been found that genetic code contains several layers of such additional information and that synonymous codons are strategically placed within mRNAs to ensure a particular translation kinetics facilitating and fine-tuning co-translational protein folding in the cell via step-wise/sequential structuring of distinct regions of the polypeptide chain emerging from the ribosome at different points in time. This review summarizes key findings in the field that have identified the role of synonymous codons and their usage in protein folding in the cell.
    MeSH term(s) Animals ; Codon/metabolism ; Escherichia coli ; Genetic Code ; Humans ; Mice ; Peptides/metabolism ; Phosphoglycerate Kinase/chemistry ; Protein Biosynthesis ; Protein Folding ; Proteins/chemistry ; RNA, Messenger/metabolism ; Ribosomes/metabolism ; Saccharomyces cerevisiae
    Chemical Substances Codon ; Peptides ; Proteins ; RNA, Messenger ; Phosphoglycerate Kinase (EC 2.7.2.3)
    Language English
    Publishing date 2021-09-03
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1109-5
    ISSN 1608-3040 ; 0006-2979 ; 0320-9717
    ISSN (online) 1608-3040
    ISSN 0006-2979 ; 0320-9717
    DOI 10.1134/S0006297921080083
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  4. Article ; Online: Molecular Peptide Grafting as a Tool to Create Novel Protein Therapeutics

    Anton A. Komar

    Molecules, Vol 28, Iss 2383, p

    2023  Volume 2383

    Abstract: The study of peptides (synthetic or corresponding to discrete regions of proteins) has facilitated the understanding of protein structure–activity relationships. Short peptides can also be used as powerful therapeutic agents. However, the functional ... ...

    Abstract The study of peptides (synthetic or corresponding to discrete regions of proteins) has facilitated the understanding of protein structure–activity relationships. Short peptides can also be used as powerful therapeutic agents. However, the functional activity of many short peptides is usually substantially lower than that of their parental proteins. This is (as a rule) due to their diminished structural organization, stability, and solubility often leading to an enhanced propensity for aggregation. Several approaches have emerged to overcome these limitations, which are aimed at imposing structural constraints into the backbone and/or sidechains of the therapeutic peptides (such as molecular stapling, peptide backbone circularization and molecular grafting), therefore enforcing their biologically active conformation and thus improving their solubility, stability, and functional activity. This review provides a short summary of approaches aimed at enhancing the biological activity of short functional peptides with a particular focus on the peptide grafting approach, whereby a functional peptide is inserted into a scaffold molecule. Intra-backbone insertions of short therapeutic peptides into scaffold proteins have been shown to enhance their activity and render them a more stable and biologically active conformation.
    Keywords peptide therapeutics ; molecular peptide grafting ; hydrogen bond surrogates ; molecular staples ; cyclic peptides ; cyclotides ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Book: Single nucleotide polymorphisms

    Komar, Anton A.

    methods and protocols

    (Methods in molecular biology ; 578 ; Springer protocols)

    2009  

    Author's details ed. by Anton A. Komar
    Series title Methods in molecular biology ; 578
    Springer protocols
    Collection
    Language English
    Size XIV, 464 S. : Ill., graph. Darst.
    Edition 2. ed.
    Publisher Humana Press
    Publishing place Totowa, NJ
    Publishing country United States
    Document type Book
    HBZ-ID HT015985719
    ISBN 978-1-60327-410-4 ; 9781603274111 ; 1-60327-410-3 ; 1603274111
    Database Catalogue ZB MED Medicine, Health

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    Shelf markLoan statusLocation
    2009 A 5529 order for loan Magazin

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  6. Article ; Online: Translation Rates and Protein Folding.

    Komar, Anton A / Samatova, Ekaterina / Rodnina, Marina V

    Journal of molecular biology

    2023  , Page(s) 168384

    Abstract: The mRNA coding sequence defines not only the amino acid sequence of the protein, but also the speed at which the ribosomes move along the mRNA while making the protein. The non-uniform local kinetics - denoted as translational rhythm - is similar among ... ...

    Abstract The mRNA coding sequence defines not only the amino acid sequence of the protein, but also the speed at which the ribosomes move along the mRNA while making the protein. The non-uniform local kinetics - denoted as translational rhythm - is similar among mRNAs coding for related protein folds. Deviations from this conserved rhythm can result in protein misfolding. In this review we summarize the experimental evidence demonstrating how local translation rates affect cotranslational protein folding, with the focus on the synonymous codons and patches of charged residues in the nascent peptide as best-studied examples. Alterations in nascent protein conformations due to disturbed translational rhythm can persist off the ribosome, as demonstrated by the effects of synonymous codon variants of several disease-related proteins. Charged amino acid patches in nascent chains also modulate translation and cotranslational protein folding, and can abrogate translation when placed at the N-terminus of the nascent peptide. During cotranslational folding, incomplete nascent chains navigate through a unique conformational landscape in which earlier intermediate states become inaccessible as the nascent peptide grows. Precisely tuned local translation rates, as well as interactions with the ribosome, guide the folding pathway towards the native structure, whereas deviations from the natural translation rhythm may favor pathways leading to trapped misfolded states. Deciphering the 'folding code' of the mRNA will contribute to understanding the diseases caused by protein misfolding and to rational protein design.
    Language English
    Publishing date 2023-12-06
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2023.168384
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    Zs.A 867: Show issues Location:
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  7. Article ; Online: How the ribosome shapes cotranslational protein folding.

    Samatova, Ekaterina / Komar, Anton A / Rodnina, Marina V

    Current opinion in structural biology

    2023  Volume 84, Page(s) 102740

    Abstract: During protein synthesis, the growing nascent peptide chain moves inside the polypeptide exit tunnel of the ribosome from the peptidyl transferase center towards the exit port where it emerges into the cytoplasm. The ribosome defines the unique energy ... ...

    Abstract During protein synthesis, the growing nascent peptide chain moves inside the polypeptide exit tunnel of the ribosome from the peptidyl transferase center towards the exit port where it emerges into the cytoplasm. The ribosome defines the unique energy landscape of the pioneering round of protein folding. The spatial confinement and the interactions of the nascent peptide with the tunnel walls facilitate formation of secondary structures, such as α-helices. The vectorial nature of protein folding inside the tunnel favors local intra- and inter-molecular interactions, thereby inducing cotranslational folding intermediates that do not form upon protein refolding in solution. Tertiary structures start to fold in the lower part of the tunnel, where interactions with the ribosome destabilize native protein folds. The present review summarizes the recent progress in understanding the driving forces of nascent protein folding inside the tunnel and at the surface of the ribosome.
    MeSH term(s) Protein Folding ; Ribosomes/metabolism ; Protein Biosynthesis ; Proteins/metabolism ; Peptides/metabolism
    Chemical Substances Proteins ; Peptides
    Language English
    Publishing date 2023-12-09
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1068353-7
    ISSN 1879-033X ; 0959-440X
    ISSN (online) 1879-033X
    ISSN 0959-440X
    DOI 10.1016/j.sbi.2023.102740
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    Zs.A 3206: Show issues Location:
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  8. Article ; Online: Unraveling co-translational protein folding: Concepts and methods.

    Komar, Anton A

    Methods (San Diego, Calif.)

    2017  Volume 137, Page(s) 71–81

    Abstract: Advances in techniques such as nuclear magnetic resonance spectroscopy, cryo-electron microscopy, and single-molecule and time-resolved fluorescent approaches are transforming our ability to study co-translational protein folding both in vivo in living ... ...

    Abstract Advances in techniques such as nuclear magnetic resonance spectroscopy, cryo-electron microscopy, and single-molecule and time-resolved fluorescent approaches are transforming our ability to study co-translational protein folding both in vivo in living cells and in vitro in reconstituted cell-free translation systems. These approaches provide comprehensive information on the spatial organization and dynamics of nascent polypeptide chains and the kinetics of co-translational protein folding. This information has led to an improved understanding of the process of protein folding in living cells and should allow remaining key questions in the field, such as what structures are formed within nascent chains during protein synthesis and when, to be answered. Ultimately, studies using these techniques will facilitate development of a unified concept of protein folding, a process that is essential for proper cell function and organism viability. This review describes current methods for analysis of co-translational protein folding with an emphasis on some of the recently developed techniques that allow monitoring of co-translational protein folding in real-time.
    MeSH term(s) Cell-Free System ; Cryoelectron Microscopy/methods ; Protein Biosynthesis/genetics ; Protein Folding ; Protein Modification, Translational/genetics ; Proteins/genetics ; Proteins/ultrastructure ; Ribosomes/genetics ; Ribosomes/ultrastructure
    Chemical Substances Proteins
    Language English
    Publishing date 2017-12-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1066584-5
    ISSN 1095-9130 ; 1046-2023
    ISSN (online) 1095-9130
    ISSN 1046-2023
    DOI 10.1016/j.ymeth.2017.11.007
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  9. Article ; Online: A Retrospective on eIF2A-and Not the Alpha Subunit of eIF2.

    Komar, Anton A / Merrick, William C

    International journal of molecular sciences

    2020  Volume 21, Issue 6

    Abstract: Initiation of protein synthesis in eukaryotes is a complex process requiring more than 12 different initiation factors, comprising over 30 polypeptide chains. The functions of many of these factors have been established in great detail; however, the ... ...

    Abstract Initiation of protein synthesis in eukaryotes is a complex process requiring more than 12 different initiation factors, comprising over 30 polypeptide chains. The functions of many of these factors have been established in great detail; however, the precise role of some of them and their mechanism of action is still not well understood. Eukaryotic initiation factor 2A (eIF2A) is a single chain 65 kDa protein that was initially believed to serve as the functional homologue of prokaryotic IF2, since eIF2A and IF2 catalyze biochemically similar reactions, i.e., they stimulate initiator Met-tRNA
    MeSH term(s) Animals ; Carrier Proteins/metabolism ; Eukaryotic Initiation Factor-2/chemistry ; Eukaryotic Initiation Factor-2/genetics ; Eukaryotic Initiation Factor-2/metabolism ; Evolution, Molecular ; Gene Knockdown Techniques ; Humans ; Mammals ; Mice, Knockout ; Peptide Chain Initiation, Translational ; Prokaryotic Initiation Factor-2/chemistry ; Prokaryotic Initiation Factor-2/metabolism ; Protein Binding ; Protein Biosynthesis ; RNA, Messenger/chemistry ; RNA, Messenger/metabolism ; RNA, Transfer/metabolism ; Signal Transduction ; Stress, Physiological ; Structure-Activity Relationship ; Transcription Initiation Site ; Yeasts/genetics ; Yeasts/metabolism
    Chemical Substances Carrier Proteins ; Eukaryotic Initiation Factor-2 ; Prokaryotic Initiation Factor-2 ; RNA, Messenger ; RNA, Transfer (9014-25-9)
    Language English
    Publishing date 2020-03-17
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21062054
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  10. Article: The "periodic table" of the genetic code: A new way to look at the code and the decoding process.

    Komar, Anton A

    Translation (Austin, Tex.)

    2016  Volume 4, Issue 2, Page(s) e1234431

    Abstract: Henri Grosjean and Eric Westhof recently presented an information-rich, alternative view of the genetic code, which takes into account current knowledge of the decoding process, including the complex nature of interactions between mRNA, tRNA and rRNA ... ...

    Abstract Henri Grosjean and Eric Westhof recently presented an information-rich, alternative view of the genetic code, which takes into account current knowledge of the decoding process, including the complex nature of interactions between mRNA, tRNA and rRNA that take place during protein synthesis on the ribosome, and it also better reflects the evolution of the code. The new asymmetrical circular genetic code has a number of advantages over the traditional codon table and the previous circular diagrams (with a symmetrical/clockwise arrangement of the U, C, A, G bases). Most importantly, all sequence co-variances can be visualized and explained based on the internal logic of the thermodynamics of codon-anticodon interactions.
    Language English
    Publishing date 2016-09-09
    Publishing country United States
    Document type Journal Article
    ISSN 2169-074X
    ISSN 2169-074X
    DOI 10.1080/21690731.2016.1234431
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