Tailoring chimeric ligands for studying and biasing ErbB receptor family interactions.

TitleTailoring chimeric ligands for studying and biasing ErbB receptor family interactions.
Publication TypeJournal Article
Year of Publication2014
AuthorsKrueger, AT, Kroll, C, Sanchez, E, Griffith, LG, Imperiali, B
JournalAngew Chem Int Ed Engl
Volume53
Issue10
Pagination2662-6
Date Published2014 Mar 3
ISSN1521-3773
Abstract

Described is the development and application of a versatile semisynthetic strategy, based on a combination of sortase-mediated coupling and tetrazine ligation chemistry, which can be exploited for the efficient incorporation of tunable functionality into chimeric recombinant proteins. To demonstrate the scope of the method, the assembly of a set of bivalent ligands, which integrate members of the epidermal growth factor (EGF) ligand family, is described. By using a series of bivalent EGFs with variable intraligand spacing, the differences in structure were correlated with the ability to bias signaling in the ErbB receptor family in a cell motility assay. Biasing away from EGFR-HER2 dimerization with a bivalent EGF was observed to reduce cell motility in an intraligand distance-dependent fashion, thus demonstrating the utility of the approach for acutely perturbing receptor-mediated cell signaling pathways.

DOI10.1002/anie.201307869
Alternate JournalAngew. Chem. Int. Ed. Engl.
PubMed ID24481645
Grant List5-T32-ES007020 / ES / NIEHS NIH HHS / United States
R01 DE019523 / DE / NIDCR NIH HHS / United States
R01DE019523-13 / DE / NIDCR NIH HHS / United States
T32 ES007020 / ES / NIEHS NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States
U54-CA112967 / CA / NCI NIH HHS / United States