5KN5

TGFalpha/Epiregulin complex with neutralizing antibody LY3016859

Summary for 5KN5

• Entry DOI: 10.2210/pdb5kn5/pdb
• Descriptor: Epiregulin Antibody LY3016859 Fab Heavy Chain, Epiregulin Antibody LY3016859 Fab Light Chain, Protransforming growth factor alpha, ... (6 entities in total)
• Functional Keywords: tgfalpha epiregulin antibody fab, immune system
• Biological source: Homo sapiens; More
• Cellular location: Transforming growth factor alpha: Secreted, extracellular space. Protransforming growth factor alpha: Cell membrane; Single-pass type I membrane protein: P01135
• Total number of polymer chains: 6
• Total formula weight: 103360.96

Authors

Atwell, S.,Boyles, J.S.,Clawson, D.K.,Druzina, Z.,Josef, G.H.,Weichert, K.,Witcher, D.R. (deposition date: 2016-06-27, release date: 2016-08-31, Last modification date: 2024-11-06)

Primary citation

Boyles, J.S.,Atwell, S.,Druzina, Z.,Heuer, J.G.,Witcher, D.R.
Structural basis of selectivity and neutralizing activity of a TGF alpha /epiregulin specific antibody.
Protein Sci., 25:2028-2036, 2016

PubMed Abstract: Recent studies have implicated a role of the epidermal growth factor receptor (EGFR) pathway in kidney disease. Skin toxicity associated with therapeutics which completely block the EGFR pathway precludes their use in chronic dosing. Therefore, we developed antibodies which specifically neutralize the EGFR ligands TGFα (transforming growth factor-alpha) and epiregulin but not EGF (epidermal growth factor), amphiregulin, betacellulin, HB-EGF (heparin-binding epidermal growth factor), or epigen. The epitope of one such neutralizing antibody, LY3016859, was characterized in detail to elucidate the structural basis for ligand specificity. Here we report a crystal structure of the LY3016859 Fab fragment in complex with soluble human TGFα. Our data demonstrate a conformational epitope located primarily within the C-terminal subdomain of the ligand. In addition, point mutagenesis experiments were used to highlight specific amino acids which are critical for both antigen binding and neutralization, most notably Ala , Glu , and His . These results illustrate the structural basis for the ligand specificity/selectivity of LY3016859 and could also provide insight into further engineering to alter specificity and/or affinity of LY3016859.

PubMed: 27543934
DOI: 10.1002/pro.3023

Experimental method

X-RAY DIFFRACTION (2.8 Å)