6QDR

Crystal structure of 14-3-3sigma in complex with a PAK6 pT99 phosphopeptide

Summary for 6QDR

• Entry DOI: 10.2210/pdb6qdr/pdb
• Descriptor: 14-3-3 protein sigma, Serine/threonine-protein kinase PAK 6, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: neuron regeneration, ppi, phosphorylation, chaperone
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 28049.16

Authors

Andrei, S.A.,Kaplan, A.,Fournier, A.E.,Ottman, C. (deposition date: 2019-01-02, release date: 2020-01-29, Last modification date: 2024-10-23)

Primary citation

Kaplan, A.,Andrei, S.A.,van Regteren Altena, A.,Simas, T.,Banerjee, S.L.,Kato, N.,Bisson, N.,Higuchi, Y.,Ottmann, C.,Fournier, A.E.
Polypharmacological Perturbation of the 14-3-3 Adaptor Protein Interactome Stimulates Neurite Outgrowth.
Cell Chem Biol, 27:657-667.e6, 2020

PubMed Abstract: Targeting protein-protein interactions (PPIs) is a promising approach in the development of drugs for many indications. 14-3-3 proteins are a family of phosphoprotein-binding molecules with critical functions in dozens of cell signaling networks. 14-3-3s are abundant in the central nervous system, and the small molecule fusicoccin-A (FC-A), a tool compound that can be used to manipulate 14-3-3 PPIs, enhances neurite outgrowth in cultured neurons. New semisynthetic FC-A derivatives with improved binding affinity for 14-3-3 complexes have recently been developed. Here, we use a series of screens that identify these compounds as potent inducers of neurite outgrowth through a polypharmacological mechanism. Using proteomics and X-ray crystallography, we discover that these compounds extensively regulate the 14-3-3 interactome by stabilizing specific PPIs, while disrupting others. These results provide new insights into the development of drugs to target 14-3-3 PPIs, a potential therapeutic strategy for CNS diseases.

PubMed: 32220335
DOI: 10.1016/j.chembiol.2020.02.010

Experimental method

X-RAY DIFFRACTION (1.615 Å)