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Title: Structures of Adnectin/Protein Complexes Reveal an Expanded Binding Footprint

Adnectins are targeted biologics derived from the tenth type III domain of human fibronectin ({sup 10}Fn3), a member of the immunoglobulin superfamily. Target-specific binders are selected from libraries generated by diversifying the three {sup 10}Fn3 loops that are analogous to the complementarity determining regions of antibodies. The crystal structures of two Adnectins were determined, each in complex with its therapeutic target, EGFR or IL-23. Both Adnectins bind different epitopes than those bound by known monoclonal antibodies. Molecular modeling suggests that some of these epitopes might not be accessible to antibodies because of the size and concave shape of the antibody combining site. In addition to interactions from the Adnectin diversified loops, residues from the N terminus and/or the {beta} strands interact with the target proteins in both complexes. Alanine-scanning mutagenesis confirmed the calculated binding energies of these {beta} strand interactions, indicating that these nonloop residues can expand the available binding footprint.
Authors:
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  1. (BMS)
Publication Date:
OSTI Identifier:
1039786
Resource Type:
Journal Article
Resource Relation:
Journal Name: Structure; Journal Volume: 20; Journal Issue: (2) ; 02, 2012
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
INDUSTRYOTHER U.S. STATES
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ANTIBODIES; BINDERS; CRYSTAL STRUCTURE; IMMUNOGLOBULINS; MONOCLONAL ANTIBODIES; MUTAGENESIS; PROTEINS; RESIDUES; SHAPE; SIMULATION; TARGETS