6QDU
Crystal structure of 14-3-3sigma in complex with a RapGef2 pT740 phosphopeptide inhibited by semi-synthetic fusicoccane FC-NCPC
Summary for 6QDU
| Entry DOI | 10.2210/pdb6qdu/pdb |
| Descriptor | 14-3-3 protein sigma, FC-NCPC, PHOSPHOTHREONINE, ... (6 entities in total) |
| Functional Keywords | neuron regeneration, ppi, phosphorylation, chaperone |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 27487.28 |
| Authors | Andrei, S.A.,Kaplan, A.,Fournier, A.E.,Ottman, C. (deposition date: 2019-01-02, release date: 2020-01-29, Last modification date: 2024-01-24) |
| 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 Cited by 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: 32220335DOI: 10.1016/j.chembiol.2020.02.010 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.632 Å) |
Structure validation
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