8c2e

From Proteopedia

Structure of 14-3-3 sigma delta C with electrophilic peptide 4IEA-5

Structural highlights

8c2e is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

1433S_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression.

Publication Abstract from PubMed

Peptide-based covalent probes can target shallow protein surfaces not typically addressable using small molecules, yet there is a need for versatile approaches to convert native peptide sequences into covalent binders that can target a broad range of residues. Here we report protein-based thio-methacrylate esters-electrophiles that can be installed easily on unprotected peptides and proteins via cysteine side chains, and react efficiently and selectively with cysteine and lysine side chains on the target. Methacrylate phosphopeptides derived from 14-3-3-binding proteins irreversibly label 14-3-3sigma via either lysine or cysteine residues, depending on the position of the electrophile. Methacrylate peptides targeting a conserved lysine residue exhibit pan-isoform binding of 14-3-3 proteins both in lysates and in extracellular media. Finally, we apply this approach to develop protein-based covalent binders. A methacrylate-modified variant of the colicin E9 immunity protein irreversibly binds to the E9 DNAse, resulting in significantly higher thermal stability relative to the non-covalent complex. Our approach offers a simple and versatile route to convert peptides and proteins into potent covalent binders.

A simple method for developing lysine targeted covalent protein reagents.,Gabizon R, Tivon B, Reddi RN, van den Oetelaar MCM, Amartely H, Cossar PJ, Ottmann C, London N Nat Commun. 2023 Dec 1;14(1):7933. doi: 10.1038/s41467-023-42632-5. PMID:38040731^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gabizon R, Tivon B, Reddi RN, van den Oetelaar MCM, Amartely H, Cossar PJ, Ottmann C, London N. A simple method for developing lysine targeted covalent protein reagents. Nat Commun. 2023 Dec 1;14(1):7933. PMID:38040731 doi:10.1038/s41467-023-42632-5