posted on 2021-08-24, 13:34authored byXavier Guillory, Inesa Hadrović, Pim J. de Vink, Andrea Sowislok, Luc Brunsveld, Thomas Schrader, Christian Ottmann
Rational
design of protein–protein interaction (PPI) inhibitors
is challenging. Connecting a general supramolecular protein binder
with a specific peptidic ligand provides a novel conceptual approach.
Thus, lysine-specific molecular tweezers were conjugated to a peptide-based
14–3–3 ligand and produced a strong PPI inhibitor with
100-fold elevated protein affinity. X-ray crystal structure elucidation
of this supramolecular directed assembly provides unique molecular
insight into the binding mode and fully aligns with Molecular Dynamics
(MD) simulations. This new supramolecular chemical biology concept
opens the path to novel chemical tools for studying PPIs.