 |
PDBsum entry 4hrm
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/de novo protein
|
PDB id
|
|
|
|
4hrm
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
166 a.a.
|
|
|
|
|
|
|
|
|
|
|
139 a.a.
|
|
|
|
|
|
|
|
|
|
|
123 a.a.
|
|
|
|
|
|
|
|
|
|
|
119 a.a.
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural basis for eliciting a cytotoxic effect in her2-Overexpressing cancer cells via binding to the extracellular domain of her2.
|
|
|
Authors
|
|
C.Jost,
J.Schilling,
R.Tamaskovic,
M.Schwill,
A.Honegger,
A.Plückthun.
|
|
|
Ref.
|
|
Structure, 2013,
21,
1979-1991.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Human epidermal growth factor receptor-2 (HER2) is a receptor tyrosine kinase
directly linked to the growth of malignancies from various origins and a
validated target for monoclonal antibodies and kinase inhibitors. Utilizing a
new approach with designed ankyrin repeat proteins (DARPins) as alternative
binders, we show that binding of two DARPins connected by a short linker, one
targeting extracellular subdomain I and the other subdomain IV, causes much
stronger cytotoxic effects on the HER2-addicted breast cancer cell line BT474,
surpassing the therapeutic antibody trastuzumab. We determined crystal
structures of these DARPins in complex with the respective subdomains. Detailed
models of the full-length receptor, constrained by its rigid domain structures
and its membrane anchoring, explain how the bispecific DARPins connect two
membrane-bound HER2 molecules, distorting them such that they cannot form
signaling-competent dimers with any EGFR family member, preventing any kinase
dimerization, and thus leading to a complete loss of signaling.
|
|
|
|
|
|
|
