LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 10 of total 39

Search options

  1. Article ; Online: Discovery and characterization of cyclic peptides selective for the C-terminal bromodomains of BET family proteins.

    Franck, Charlotte / Patel, Karishma / Walport, Louise J / Christie, Mary / Norman, Alexander / Passioura, Toby / Suga, Hiroaki / Payne, Richard J / Mackay, Joel P

    Structure (London, England : 1993)

    2023  Volume 31, Issue 8, Page(s) 912–923.e4

    Abstract: DNA-encoded cyclic peptide libraries can yield high-potency, high-specificity ligands against target proteins. We used such a library to seek ligands that could distinguish between paralogous bromodomains from the closely related bromodomain and extra- ... ...

    Abstract DNA-encoded cyclic peptide libraries can yield high-potency, high-specificity ligands against target proteins. We used such a library to seek ligands that could distinguish between paralogous bromodomains from the closely related bromodomain and extra-terminal domain family of epigenetic regulators. Several peptides isolated from a screen against the C-terminal bromodomain of BRD2, together with new peptides discovered in previous screens against the corresponding domain from BRD3 and BRD4, bound their targets with nanomolar and sub-nanomolar affinities. X-ray crystal structures of several of these bromodomain-peptide complexes reveal diverse structures and binding modes, which nevertheless display several conserved features. Some peptides demonstrate significant paralog-level specificity, although the physicochemical explanations for this specificity are often not clear. Our data demonstrate the power of cyclic peptides to discriminate between very similar proteins with high potency and hint that differences in conformational dynamics might modulate the affinity of these domains for particular ligands.
    MeSH term(s) Transcription Factors/metabolism ; Nuclear Proteins/metabolism ; Peptides, Cyclic ; Ligands ; Protein Domains ; Cell Cycle Proteins/metabolism
    Chemical Substances Transcription Factors ; Nuclear Proteins ; Peptides, Cyclic ; Ligands ; Cell Cycle Proteins
    Language English
    Publishing date 2023-06-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1213087-4
    ISSN 1878-4186 ; 0969-2126
    ISSN (online) 1878-4186
    ISSN 0969-2126
    DOI 10.1016/j.str.2023.05.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  2. Article ; Online: Evaluation of Peptide Ligation Strategies for the Synthesis of the Bivalent Acid-Sensing Ion Channel Inhibitor Hi1a.

    Tran, Hue N T / Budusan, Elena / Saez, Natalie J / Norman, Alexander / Tucker, Isaac J / King, Glenn F / Payne, Richard J / Rash, Lachlan D / Vetter, Irina / Schroeder, Christina I

    Organic letters

    2023  Volume 25, Issue 24, Page(s) 4439–4444

    Abstract: Hi1a is a naturally occurring bivalent spider-venom peptide that is being investigated as a promising molecule for limiting ischemic damage in strokes, myocardial infarction, and organ transplantation. However, the challenges associated with the ... ...

    Abstract Hi1a is a naturally occurring bivalent spider-venom peptide that is being investigated as a promising molecule for limiting ischemic damage in strokes, myocardial infarction, and organ transplantation. However, the challenges associated with the synthesis and production of the peptide in large quantities have slowed the progress in this area; hence, access to synthetic Hi1a is an essential milestone for the development of Hi1a as a pharmacological tool and potential therapeutic.
    MeSH term(s) Acid Sensing Ion Channels ; Ligation ; Peptides/chemistry ; Spider Venoms/metabolism ; Spider Venoms/pharmacology ; Ischemic Stroke/physiopathology ; Myocardial Infarction/physiopathology
    Chemical Substances Acid Sensing Ion Channels ; Peptides ; Spider Venoms
    Language English
    Publishing date 2023-06-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
    ISSN 1523-7052
    ISSN (online) 1523-7052
    DOI 10.1021/acs.orglett.3c01346
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  3. Article ; Online: Changes in Potency and Subtype Selectivity of Bivalent Na

    Tran, Poanna / Tran, Hue N T / McMahon, Kirsten L / Deuis, Jennifer R / Ragnarsson, Lotten / Norman, Alexander / Sharpe, Simon J / Payne, Richard J / Vetter, Irina / Schroeder, Christina I

    Bioconjugate chemistry

    2023  Volume 34, Issue 6, Page(s) 1072–1083

    Abstract: Disulfide-rich peptide toxins have long been studied for their ability to inhibit voltage-gated sodium channel subtype ... ...

    Abstract Disulfide-rich peptide toxins have long been studied for their ability to inhibit voltage-gated sodium channel subtype Na
    MeSH term(s) Humans ; Peptides/pharmacology
    Chemical Substances Peptides
    Language English
    Publishing date 2023-06-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
    ZDB-ID 1024041-x
    ISSN 1520-4812 ; 1043-1802
    ISSN (online) 1520-4812
    ISSN 1043-1802
    DOI 10.1021/acs.bioconjchem.3c00135
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  4. Article ; Online: Cross-linking mass spectrometry discovers, evaluates, and corroborates structures and protein-protein interactions in the human cell.

    Bartolec, Tara K / Vázquez-Campos, Xabier / Norman, Alexander / Luong, Clement / Johnson, Marcus / Payne, Richard J / Wilkins, Marc R / Mackay, Joel P / Low, Jason K K

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 17, Page(s) e2219418120

    Abstract: Significant recent advances in structural biology, particularly in the field of cryoelectron microscopy, have dramatically expanded our ability to create structural models of proteins and protein complexes. However, many proteins remain refractory to ... ...

    Abstract Significant recent advances in structural biology, particularly in the field of cryoelectron microscopy, have dramatically expanded our ability to create structural models of proteins and protein complexes. However, many proteins remain refractory to these approaches because of their low abundance, low stability, or-in the case of complexes-simply not having yet been analyzed. Here, we demonstrate the power of using cross-linking mass spectrometry (XL-MS) for the high-throughput experimental assessment of the structures of proteins and protein complexes. This included those produced by high-resolution but in vitro experimental data, as well as in silico predictions based on amino acid sequence alone. We present the largest XL-MS dataset to date, describing 28,910 unique residue pairs captured across 4,084 unique human proteins and 2,110 unique protein-protein interactions. We show that models of proteins and their complexes predicted by AlphaFold2, and inspired and corroborated by the XL-MS data, offer opportunities to deeply mine the structural proteome and interactome and reveal mechanisms underlying protein structure and function.
    MeSH term(s) Humans ; Cryoelectron Microscopy ; Proteomics/methods ; Mass Spectrometry/methods ; Molecular Biology/methods ; Proteome/chemistry ; Cross-Linking Reagents/chemistry
    Chemical Substances Proteome ; Cross-Linking Reagents
    Language English
    Publishing date 2023-04-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2219418120
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  5. Article ; Online: Sustainability of an Enhanced Recovery After Surgery initiative for elective colorectal resections in a community hospital.

    Norman, Alexander / Mahoney, Krista / Ballah, Erin / Pridham, Jeremy / Smith, Chris / Parfrey, Patrick

    Canadian journal of surgery. Journal canadien de chirurgie

    2020  Volume 63, Issue 3, Page(s) E292–E298

    Abstract: Background: In March 2016, an Enhanced Recovery After Surgery (ERAS) initiative was implemented for all elective colorectal resections at an urban hospital in St. John's, Newfoundland and Labrador, Canada. An ERAS coordinator supervised and enforced ... ...

    Abstract Background: In March 2016, an Enhanced Recovery After Surgery (ERAS) initiative was implemented for all elective colorectal resections at an urban hospital in St. John's, Newfoundland and Labrador, Canada. An ERAS coordinator supervised and enforced guideline compliance for 6 months. The aim of this study was to evaluate the sustainability of the ERAS program after supervision of guideline compliance was eliminated.
    Methods: Patient outcomes and guideline compliance were compared between surgeries performed under standard practice (April 2014 to March 2015) and those performed during and after the implementation of the ERAS initiative (March 2016 to August 2016 was the implementation phase and September 2016 to February 2017 was the sustainability phase).
    Results: Hospital length of stay decreased from 7.26 days at baseline to 5.44 days during the implementation phase of the ERAS program (p < 0.001). There was no significant difference between length of stay at baseline and during the 6-month sustainability phase of the ERAS program (7.10 d). There were no significant differences in rates of readmission or mortality during and after implementation. Rate of ileus decreased significantly from 13.8% during the implementation phase to 4.6% during the sustainability phase (p = 0.036). Total guideline compliance increased from 52.2% at baseline to 80.7% during the implementation phase (p < 0.001), and decreased to 74.7% during the sustainability phase (p < 0.001). Adherence to postoperative guidelines regressed: 79.2% in the implementation phase and 68.6% in the sustainability phase (p < 0.001).
    Conclusion: La durée des séjours à l’hôpital a diminué après l’adoption du programme de RAAC, lorsque le coordonnateur du programme était présent. Les méthodes de maintien des lignes directrices après leur adoption seront cruciales au succès de programmes similaires à l’avenir.
    MeSH term(s) Aged ; Canada/epidemiology ; Clinical Protocols ; Colectomy/methods ; Colorectal Neoplasms/surgery ; Elective Surgical Procedures/methods ; Enhanced Recovery After Surgery/standards ; Female ; Follow-Up Studies ; Guideline Adherence ; Hospitals, Community/statistics & numerical data ; Humans ; Incidence ; Length of Stay/trends ; Male ; Middle Aged ; Perioperative Care/methods ; Postoperative Complications/epidemiology ; Program Evaluation ; Retrospective Studies
    Language English
    Publishing date 2020-05-21
    Publishing country Canada
    Document type Journal Article
    ZDB-ID 410651-9
    ISSN 1488-2310 ; 0008-428X
    ISSN (online) 1488-2310
    ISSN 0008-428X
    DOI 10.1503/cjs.016018
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  6. Article ; Online: mRNA display reveals a class of high-affinity bromodomain-binding motifs that are not found in the human proteome.

    Low, Jason K K / Patel, Karishma / Jones, Natasha / Solomon, Paul / Norman, Alexander / Maxwell, Joshua W C / Pachl, Petr / Matthews, Jacqueline M / Payne, Richard J / Passioura, Toby / Suga, Hiroaki / Walport, Louise J / Mackay, Joel P

    The Journal of biological chemistry

    2023  Volume 299, Issue 12, Page(s) 105482

    Abstract: Bromodomains (BDs) regulate gene expression by recognizing protein motifs containing acetyllysine. Although originally characterized as histone-binding proteins, it has since become clear that these domains interact with other acetylated proteins, ... ...

    Abstract Bromodomains (BDs) regulate gene expression by recognizing protein motifs containing acetyllysine. Although originally characterized as histone-binding proteins, it has since become clear that these domains interact with other acetylated proteins, perhaps most prominently transcription factors. The likely transient nature and low stoichiometry of such modifications, however, has made it challenging to fully define the interactome of any given BD. To begin to address this knowledge gap in an unbiased manner, we carried out mRNA display screens against a BD-the N-terminal BD of BRD3-using peptide libraries that contained either one or two acetyllysine residues. We discovered peptides with very strong consensus sequences and with affinities that are significantly higher than typical BD-peptide interactions. X-ray crystal structures also revealed modes of binding that have not been seen with natural ligands. Intriguingly, however, our sequences are not found in the human proteome, perhaps suggesting that strong binders to BDs might have been selected against during evolution.
    MeSH term(s) Humans ; Proteome/metabolism ; Transcription Factors/metabolism ; Protein Domains ; Amino Acid Motifs ; Peptides/metabolism ; Protein Binding ; Acetylation
    Chemical Substances Proteome ; Transcription Factors ; Peptides
    Language English
    Publishing date 2023-11-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2023.105482
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  7. Book: Holder of the white lotus

    Norman, Alexander

    the lives of the Dalai Lama

    2008  

    Author's details Alexander Norman
    Language English
    Size XVIII, 446 S.
    Publisher Little, Brown
    Publishing place London
    Document type Book
    ISBN 0316859885 ; 9780316859882
    Database Former special subject collection: coastal and deep sea fishing

    More links

    Kategorien

  8. Article: Expressed Protein Selenoester Ligation.

    Kulkarni, Sameer S / Watson, Emma E / Maxwell, Joshua W C / Niederacher, Gerhard / Johansen-Leete, Jason / Huhmann, Susanne / Mukherjee, Somnath / Norman, Alexander R / Kriegesmann, Julia / Becker, Christian F W / Payne, Richard J

    Angewandte Chemie (Weinheim an der Bergstrasse, Germany)

    2022  Volume 134, Issue 20, Page(s) e202200163

    Abstract: Herein, we describe the development and application of a novel expressed protein selenoester ligation (EPSL) methodology for the one-pot semi-synthesis of modified proteins. EPSL harnesses the rapid kinetics of ligation reactions between modified ... ...

    Abstract Herein, we describe the development and application of a novel expressed protein selenoester ligation (EPSL) methodology for the one-pot semi-synthesis of modified proteins. EPSL harnesses the rapid kinetics of ligation reactions between modified synthetic selenopeptides and protein aryl selenoesters (generated from expressed intein fusion precursors) followed by in situ chemoselective deselenization to afford target proteins at concentrations that preclude the use of traditional ligation methods. The utility of the EPSL technology is showcased through the efficient semi-synthesis of ubiquitinated polypeptides, lipidated analogues of the membrane-associated GTPase YPT6, and site-specifically phosphorylated variants of the oligomeric chaperone protein Hsp27 at high dilution.
    Language English
    Publishing date 2022-03-09
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 506609-8
    ISSN 1521-3757 ; 0044-8249 ; 0932-2140
    ISSN (online) 1521-3757
    ISSN 0044-8249 ; 0932-2140
    DOI 10.1002/ange.202200163
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  9. Article ; Online: Expressed Protein Selenoester Ligation.

    Kulkarni, Sameer S / Watson, Emma E / Maxwell, Joshua W C / Niederacher, Gerhard / Johansen-Leete, Jason / Huhmann, Susanne / Mukherjee, Somnath / Norman, Alexander R / Kriegesmann, Julia / Becker, Christian F W / Payne, Richard J

    Angewandte Chemie (International ed. in English)

    2022  Volume 61, Issue 20, Page(s) e202200163

    Abstract: Herein, we describe the development and application of a novel expressed protein selenoester ligation (EPSL) methodology for the one-pot semi-synthesis of modified proteins. EPSL harnesses the rapid kinetics of ligation reactions between modified ... ...

    Abstract Herein, we describe the development and application of a novel expressed protein selenoester ligation (EPSL) methodology for the one-pot semi-synthesis of modified proteins. EPSL harnesses the rapid kinetics of ligation reactions between modified synthetic selenopeptides and protein aryl selenoesters (generated from expressed intein fusion precursors) followed by in situ chemoselective deselenization to afford target proteins at concentrations that preclude the use of traditional ligation methods. The utility of the EPSL technology is showcased through the efficient semi-synthesis of ubiquitinated polypeptides, lipidated analogues of the membrane-associated GTPase YPT6, and site-specifically phosphorylated variants of the oligomeric chaperone protein Hsp27 at high dilution.
    MeSH term(s) Peptides ; Proteins
    Chemical Substances Peptides ; Proteins
    Language English
    Publishing date 2022-03-09
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.202200163
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  10. Article ; Online: Solid-state (13)C NMR and synchrotron SAXS/WAXS studies of uniaxially-oriented polyethylene.

    Afeworki, Mobae / Brant, Pat / Lustiger, Arnold / Norman, Alexander

    Solid state nuclear magnetic resonance

    2015  Volume 72, Page(s) 27–40

    Abstract: We report solid-state (13)C NMR and synchrotron wide-and small-angle X-ray scattering experiments (WAXS, SAXS) on metallocene linear low density polyethylene films (e.g., Exceed™ 1018 mLLDPE; nominally 1MI, 0.918 density ethylene-hexene metallocene ... ...

    Abstract We report solid-state (13)C NMR and synchrotron wide-and small-angle X-ray scattering experiments (WAXS, SAXS) on metallocene linear low density polyethylene films (e.g., Exceed™ 1018 mLLDPE; nominally 1MI, 0.918 density ethylene-hexene metallocene copolymer) as a function of uniaxial draw ratio, λ. Combined, these experiments provide an unambiguous, quantitative molecular view of the orientation of both the crystalline and amorphous phases in the samples as a function of draw. Together with previously reported differential scanning calorimetry (DSC), gas transport measurements, transmission electron microscopy (TEM), optical birefringence, small angle X-ray scattering (SAXS) as well as other characterization techniques, this study of the state of orientation in both phases provides insight concerning the development of unusually high barrier properties of the most oriented samples (λ=10). In this work, static (non-spinning) solid-state NMR measurements indicate that in the drawn Exceed(TM) films both the crystalline and amorphous regions are highly oriented. In particular, chemical shift data show the amorphous phase is comprised increasingly of so-called "taut tie chains" (or tie chains under any state of tautness) in the mLLDPE with increasing draw ratio - the resonance lines associated with the amorphous phase shift to where the crystalline peaks are observed. In the sample with highest total draw (λ=10), virtually all of the chains in the non-crystalline region have responded and aligned in the machine (draw) direction. Both monoclinic and orthorhombic crystalline peaks are observed in high-resolution, solid-state magic-angle spinning (MAS) NMR measurements of the oriented PE films. The orientation is comparable to that obtained for ultra-high molecular weight HDPE fibers described as "ultra-oriented" in the literature. Furthermore, the presence of a monoclinic peak in cold-drawn samples suggests that there is an appreciable internal stress associated with the LLDPE. The results are confirmed and independently quantified by Herman's Orientation Function values derived from the WAXS measurements. The degree of orientation approaches theoretically perfect alignment of chains along the draw direction. We deduce from this observation that a high fraction of the non-crystalline chains are either tie chains that directly connect adjacent lamellae or are interlocking loops from adjacent lamellae. In either case, the chains are load-bearing and are consistent with the idea of "taut tie chains". We note that transmission electron micrographs recorded for the ultra-oriented Exceed showed the lamellae are often appreciably thinner and shorter than they are for cast or blown Exceed 1018. Combined with higher crystallinity, the thinner lamellae statistically favor more tie chains. Finally, the remarkably large decrease in permeability of the λ=10 film is primarily attributed to the high degree of orientation (and loss of entropy) of the amorphous phase.
    Language English
    Publishing date 2015-11
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1122088-0
    ISSN 1527-3326 ; 0926-2040
    ISSN (online) 1527-3326
    ISSN 0926-2040
    DOI 10.1016/j.ssnmr.2015.10.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

To top