6NV2

14-3-3 sigma with RelA/p65 binding site pS45 in complex with DP005

Summary for 6NV2

• Entry DOI: 10.2210/pdb6nv2/pdb
• Related: 6QHM
• Descriptor: 14-3-3 protein sigma, Transcription factor p65, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: fusicoccanes, natural products, p65, 1433, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 28503.43

Authors

Wolter, M.,Ottmann, C. (deposition date: 2019-02-04, release date: 2020-05-13, Last modification date: 2024-11-13)

Primary citation

Wolter, M.,de Vink, P.,Neves, J.F.,Srdanovic, S.,Higuchi, Y.,Kato, N.,Wilson, A.,Landrieu, I.,Brunsveld, L.,Ottmann, C.
Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products.
J.Am.Chem.Soc., 142:11772-11783, 2020

PubMed Abstract: 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, which qualifies this protein complex as a potential target for drug discovery 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 semisynthetic 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.

PubMed: 32501683
DOI: 10.1021/jacs.0c02151

Experimental method

X-RAY DIFFRACTION (1.13 Å)