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  1. Article ; Online: Inside-out

    Yue Pan / Indu R Chandrashekaran / Luke Tennant / Jamie Rossjohn / Dene R Littler

    PLoS ONE, Vol 18, Iss 4, p e

    Antibody-binding reveals potential folding hinge-points within the SARS-CoV-2 replication co-factor nsp9.

    2023  Volume 0283194

    Abstract: Nsp9 is a conserved accessory component of the coronaviral replication and transcription complex. It is the predominant substrate of nsp12's nucleotidylation activity while also serving to recruit proteins required for viral 5'-capping. Anti-nsp9 ... ...

    Abstract Nsp9 is a conserved accessory component of the coronaviral replication and transcription complex. It is the predominant substrate of nsp12's nucleotidylation activity while also serving to recruit proteins required for viral 5'-capping. Anti-nsp9 specific nanobodies have been isolated previously. We confirm that their binding mode is centred upon Trp-53 within SARS-CoV-2 nsp9. Antibody binding at this site surprisingly results in large-scale changes to the overall topology of this coronaviral unique fold. We further characterise the antibody-induced structural dynamism within nsp9, identifying a number of potentially flexible regions. A large expansion of the cavity between the s2-s3 and s4-s5 loops is particularly noteworthy. As is the potential for large-scale movements in the C-terminal GxxxG helix.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  2. Article ; Online: Inside-out

    Yue Pan / Indu R. Chandrashekaran / Luke Tennant / Jamie Rossjohn / Dene R. Littler

    PLoS ONE, Vol 18, Iss

    Antibody-binding reveals potential folding hinge-points within the SARS-CoV-2 replication co-factor nsp9

    2023  Volume 4

    Abstract: Nsp9 is a conserved accessory component of the coronaviral replication and transcription complex. It is the predominant substrate of nsp12’s nucleotidylation activity while also serving to recruit proteins required for viral 5’-capping. Anti-nsp9 ... ...

    Abstract Nsp9 is a conserved accessory component of the coronaviral replication and transcription complex. It is the predominant substrate of nsp12’s nucleotidylation activity while also serving to recruit proteins required for viral 5’-capping. Anti-nsp9 specific nanobodies have been isolated previously. We confirm that their binding mode is centred upon Trp-53 within SARS-CoV-2 nsp9. Antibody binding at this site surprisingly results in large-scale changes to the overall topology of this coronaviral unique fold. We further characterise the antibody-induced structural dynamism within nsp9, identifying a number of potentially flexible regions. A large expansion of the cavity between the s2-s3 and s4-s5 loops is particularly noteworthy. As is the potential for large-scale movements in the C-terminal GxxxG helix.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  3. Article ; Online: Applications of 19F-NMR in Fragment-Based Drug Discovery

    Raymond S. Norton / Eleanor W. W. Leung / Indu R. Chandrashekaran / Christopher A. MacRaild

    Molecules, Vol 21, Iss 7, p

    2016  Volume 860

    Abstract: 19F-NMR has proved to be a valuable tool in fragment-based drug discovery. Its applications include screening libraries of fluorinated fragments, assessing competition among elaborated fragments and identifying the binding poses of promising hits. By ... ...

    Abstract 19F-NMR has proved to be a valuable tool in fragment-based drug discovery. Its applications include screening libraries of fluorinated fragments, assessing competition among elaborated fragments and identifying the binding poses of promising hits. By observing fluorine in both the ligand and the target protein, useful information can be obtained on not only the binding pose but also the dynamics of ligand-protein interactions. These applications of 19F-NMR will be illustrated in this review with studies from our fragment-based drug discovery campaigns against protein targets in parasitic and infectious diseases.
    Keywords fragment-based drug design ; 19F-NMR ; labelling ; chemical shift ; linewidth ; ligand ; protein ; peptide ; Organic chemistry ; QD241-441
    Language English
    Publishing date 2016-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Pharmacophore Pattern Identification of Tachykinin Receptor Selective Peptide Agonists

    Anjali Dike / Indu R. Chandrashekaran / Anil K. Mantha / Najma Z. Baquer / Sudha M. Cowsik

    American Journal of Biochemistry and Biotechnology, Vol 3, Iss 4, Pp 180-

    Implications in Receptor Selectivity

    2007  Volume 186

    Abstract: The mammalian tachykinin (TK) peptides and their three Neurokinin (NK1, NK2 and NK3) receptors represent an effector system with wide-ranging actions on neuronal, airway smooth muscle, mucosal, endothelial, immune, inflammatory and remodeling cell ... ...

    Abstract The mammalian tachykinin (TK) peptides and their three Neurokinin (NK1, NK2 and NK3) receptors represent an effector system with wide-ranging actions on neuronal, airway smooth muscle, mucosal, endothelial, immune, inflammatory and remodeling cell function. Recent clinical and preclinical data suggests the pathophysiological role of TKs in various diseases including asthma, emesis and depression. The TK-NK receptor interactions and overlapping functions mediated by each NK receptor indicate added therapeutic benefit of using multiple NK receptor blockade. In the absence of structural data on neurokinin receptors, the membrane-induced structure of tachykinins play an important role as a first step towards understanding structure-activity relationship. A comparison of the conformational features of different NK1, NK2 and NK3 receptor agonists highlights several features which might be responsible for determining selectivity for the particular receptor subtype. An attempt has been made to correlate the observed conformational differences to the binding ability and biological activity of various NK1, NK2 and NK3 receptor agonists. The membrane bound conformations of tachykinins have been used as a starting point, leading to useful pharmacophore patterns that can be used for identifying lead structures with novel scaffolds.
    Keywords </keyword><keyword>Tachykinin ; Neuropeptide ; Neurokinin receptor ; Pharmacophore pattern ; Solution conformation ; Biochemistry ; QD415-436 ; Organic chemistry ; QD241-441 ; Chemistry ; QD1-999 ; Science ; Q ; DOAJ:Biochemistry ; DOAJ:Life Sciences ; DOAJ:Biology and Life Sciences ; Biotechnology ; TP248.13-248.65 ; Chemical technology ; TP1-1185 ; Technology ; T ; DOAJ:Biotechnology
    Subject code 540
    Language English
    Publishing date 2007-01-01T00:00:00Z
    Publisher Science Publications
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

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  5. Article ; Online: Suppressor of Cytokine Signaling (SOCS) 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1.

    Edmond M Linossi / Indu R Chandrashekaran / Tatiana B Kolesnik / James M Murphy / Andrew I Webb / Tracy A Willson / Lukasz Kedzierski / Alex N Bullock / Jeffrey J Babon / Raymond S Norton / Nicos A Nicola / Sandra E Nicholson

    PLoS ONE, Vol 8, Iss 8, p e

    2013  Volume 70536

    Abstract: Suppressor of Cytokine Signaling (SOCS)5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF) signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. ...

    Abstract Suppressor of Cytokine Signaling (SOCS)5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF) signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved region in its N-terminus, which we have termed the JAK interaction region (JIR). Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2) autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N-terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high-affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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