TY - JOUR
T1 - Selectivity via Cooperativity
T2 - Preferential Stabilization of the p65/14-3-3 interaction with Semi-Synthetic Natural Products
AU - Wolter, Madita
AU - de Vink, Pim
AU - Neves, Joao Filipe
AU - Srdanovic, Sonja
AU - Higuchi, Yusuke
AU - Kato, Nobuo
AU - Wilson, Andrew J
AU - Landrieu, Isabelle
AU - Brunsveld, Luc
AU - Ottmann, Christian
PY - 2020/7/8
Y1 - 2020/7/8
N2 - Natural compounds are an important class of potent drug molecules including some retrospectively found to act as stabilizers of protein-protein interactions (PPIs). However, the design of synthetic PPI stabilizers remains an understudied approach. To date, there are limited examples where cooperativity has been utilized to guide the optimization of a PPI stabilizer. The 14-3-3 scaffold proteins provide an excellent platform to explore PPI stabilization because these proteins mediate several hundred PPIs, and a class of natural compounds - the fusicoccanes - are known to stabilize a subset of 14-3-3 protein interactions. 14-3-3 has been reported to negatively regulate the p65 subunit of the NF-κB transcription factor, qualifying this protein complex as a potential target for drug discovery in order to control cell proliferation. Here, we report the high-resolution crystal structures of two 14-3-3 binding motifs of p65 in complex with 14-3-3. A semi-synthetic natural product derivative - DP-005 - binds to an interface pocket of the p65/14-3-3 complex and concomitantly stabilizes it. Cooperativity analyses of this interaction, and other disease relevant 14-3-3-PPIs, demonstrated selectivity of DP-005 for the p65/14-3-3 complex. The adaptation of a cooperative binding model provided a general approach to characterize stabilization and to assay for selectivity of PPI stabilizers.
AB - Natural compounds are an important class of potent drug molecules including some retrospectively found to act as stabilizers of protein-protein interactions (PPIs). However, the design of synthetic PPI stabilizers remains an understudied approach. To date, there are limited examples where cooperativity has been utilized to guide the optimization of a PPI stabilizer. The 14-3-3 scaffold proteins provide an excellent platform to explore PPI stabilization because these proteins mediate several hundred PPIs, and a class of natural compounds - the fusicoccanes - are known to stabilize a subset of 14-3-3 protein interactions. 14-3-3 has been reported to negatively regulate the p65 subunit of the NF-κB transcription factor, qualifying this protein complex as a potential target for drug discovery in order to control cell proliferation. Here, we report the high-resolution crystal structures of two 14-3-3 binding motifs of p65 in complex with 14-3-3. A semi-synthetic natural product derivative - DP-005 - binds to an interface pocket of the p65/14-3-3 complex and concomitantly stabilizes it. Cooperativity analyses of this interaction, and other disease relevant 14-3-3-PPIs, demonstrated selectivity of DP-005 for the p65/14-3-3 complex. The adaptation of a cooperative binding model provided a general approach to characterize stabilization and to assay for selectivity of PPI stabilizers.
UR - http://www.scopus.com/inward/record.url?scp=85088031195&partnerID=8YFLogxK
U2 - 10.1021/jacs.0c02151
DO - 10.1021/jacs.0c02151
M3 - Article
C2 - 32501683
SN - 0002-7863
VL - 142
SP - 11772
EP - 11783
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 27
ER -