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Rational design of Nanobody80 loop peptidomimetics : towards biased β2 adrenergic receptor ligands

Charlotte Martin, Samuel Moors, Mia Danielsen, Cecilia Betti, Cecilia Fabris, Daniel Sejer Pedersen, Els Pardon, Marion Peyressatre, Krisztina Fehér, José Martins (UGent), et al.
(2017) CHEMISTRY-A EUROPEAN JOURNAL. 23(40). p.9632-9640
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Abstract
G protein-coupled receptors (GPCRs) play an important role in many cellular responses; as such, their mechanism of action is of utmost interest. To gain insight into the active conformation of GPCRs, the X-ray crystal structures of nanobody (Nb)-stabilized beta(2)-adrenergic receptor (beta(2)AR) have been reported. Nb80, in particular, is able to bind the intracellular G protein binding site of beta(2)AR and stabilize the receptor in an active conformation. Within Nb80, the complementarity-determining region 3 (CDR3) is responsible for most of the binding interactions. Hence, we hypothesized that peptidomimetics of the CDR3 loop might be sufficient for binding to the receptor, inhibiting the interaction of beta(2)AR with intracellular GPCR interacting proteins (e. g., G proteins). Based on previous crystallographic data, a set of peptidomimetics were synthesized that, similar to the Nb80 CDR3 loop, adopt a beta-hairpin conformation. Syntheses, conformational analysis, binding and functional in vitro assays, as well as internalization experiments, were performed. We demonstrate that peptidomimetics can structurally mimic the CDR3 loop of a nanobody and its function by inhibiting G protein coupling as measured by partial inhibition of cAMP production.
Keywords
PROTEIN-PROTEIN INTERACTIONS, HEAVY-CHAIN ANTIBODIES, COUPLED RECEPTOR, EPITOPE MIMETICS, HIGH-THROUGHPUT, THERAPEUTICS, OPPORTUNITIES, INHIBITORS, RECOGNITION

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Chicago
Martin, Charlotte, Samuel Moors, Mia Danielsen, Cecilia Betti, Cecilia Fabris, Daniel Sejer Pedersen, Els Pardon, et al. 2017. “Rational Design of Nanobody80 Loop Peptidomimetics : Towards Biased Β2 Adrenergic Receptor Ligands.” Chemistry-a European Journal 23 (40): 9632–9640.
APA
Martin, Charlotte, Moors, S., Danielsen, M., Betti, C., Fabris, C., Sejer Pedersen, D., Pardon, E., et al. (2017). Rational design of Nanobody80 loop peptidomimetics : towards biased β2 adrenergic receptor ligands. CHEMISTRY-A EUROPEAN JOURNAL, 23(40), 9632–9640.
Vancouver
1.
Martin C, Moors S, Danielsen M, Betti C, Fabris C, Sejer Pedersen D, et al. Rational design of Nanobody80 loop peptidomimetics : towards biased β2 adrenergic receptor ligands. CHEMISTRY-A EUROPEAN JOURNAL. 2017;23(40):9632–40.
MLA
Martin, Charlotte, Samuel Moors, Mia Danielsen, et al. “Rational Design of Nanobody80 Loop Peptidomimetics : Towards Biased Β2 Adrenergic Receptor Ligands.” CHEMISTRY-A EUROPEAN JOURNAL 23.40 (2017): 9632–9640. Print.
@article{8522597,
  abstract     = {G protein-coupled receptors (GPCRs) play an important role in many cellular responses; as such, their mechanism of action is of utmost interest. To gain insight into the active conformation of GPCRs, the X-ray crystal structures of nanobody (Nb)-stabilized beta(2)-adrenergic receptor (beta(2)AR) have been reported. Nb80, in particular, is able to bind the intracellular G protein binding site of beta(2)AR and stabilize the receptor in an active conformation. Within Nb80, the complementarity-determining region 3 (CDR3) is responsible for most of the binding interactions. Hence, we hypothesized that peptidomimetics of the CDR3 loop might be sufficient for binding to the receptor, inhibiting the interaction of beta(2)AR with intracellular GPCR interacting proteins (e. g., G proteins). Based on previous crystallographic data, a set of peptidomimetics were synthesized that, similar to the Nb80 CDR3 loop, adopt a beta-hairpin conformation. Syntheses, conformational analysis, binding and functional in vitro assays, as well as internalization experiments, were performed. We demonstrate that peptidomimetics can structurally mimic the CDR3 loop of a nanobody and its function by inhibiting G protein coupling as measured by partial inhibition of cAMP production.},
  author       = {Martin, Charlotte and Moors, Samuel and Danielsen, Mia and Betti, Cecilia and Fabris, Cecilia and Sejer Pedersen, Daniel and Pardon, Els and Peyressatre, Marion and Feh{\'e}r, Krisztina and Martins, Jos{\'e} and Mosolff Mathiesen, Jesper and Morris, May and Devoogdt, Nick and Caveliers, Vicky and De Proft, Frank and Steyaert, Jan and Ballet, Steven},
  issn         = {0947-6539},
  journal      = {CHEMISTRY-A EUROPEAN JOURNAL},
  keyword      = {PROTEIN-PROTEIN INTERACTIONS,HEAVY-CHAIN ANTIBODIES,COUPLED RECEPTOR,EPITOPE MIMETICS,HIGH-THROUGHPUT,THERAPEUTICS,OPPORTUNITIES,INHIBITORS,RECOGNITION},
  language     = {eng},
  number       = {40},
  pages        = {9632--9640},
  title        = {Rational design of Nanobody80 loop peptidomimetics : towards biased \ensuremath{\beta}2 adrenergic receptor ligands},
  url          = {http://dx.doi.org/10.1002/chem.201701321},
  volume       = {23},
  year         = {2017},
}
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