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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
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.
Please use this url to cite or link to this publication:
author
organization
alternative title
Rational design of Nanobody80 loop peptidomimetics : towards biased beta(2) adrenergic receptor ligands
year
type
journalArticle (original)
publication status
published
subject
keyword
PROTEIN-PROTEIN INTERACTIONS, HEAVY-CHAIN ANTIBODIES, COUPLED RECEPTOR, EPITOPE MIMETICS, HIGH-THROUGHPUT, THERAPEUTICS, OPPORTUNITIES, INHIBITORS, RECOGNITION
journal title
CHEMISTRY-A EUROPEAN JOURNAL
Chem. Eur. J.
volume
23
issue
40
pages
9632 - 9640
Web of Science type
Article
Web of Science id
000405695400026
ISSN
0947-6539
DOI
10.1002/chem.201701321
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8522597
handle
http://hdl.handle.net/1854/LU-8522597
date created
2017-06-06 12:43:34
date last changed
2018-01-16 10:45:27
@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},
}

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.