PDBsum entry 4hrl

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protein Protein-protein interface(s) links
Transferase/de novo protein PDB id
Jmol PyMol
Protein chains
169 a.a.
162 a.a.
Waters ×31
PDB id:
Name: Transferase/de novo protein
Title: Structural basis for eliciting a cytotoxic effect in her2- overexpressing cancer cells via binding to the extracellula of her2
Structure: Receptor tyrosine-protein kinase erbb-2. Chain: c. Fragment: n-terminal extracellular domain i, unp residues 2 synonym: metastatic lymph node gene 19 protein, mln 19, pro oncogene neu, proto-oncogenE C-erbb-2, tyrosine kinase-type surface receptor her2, p185erbb2. Engineered: yes. Mutation: yes. Designed ankyrin repeat protein 9_29.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: erbb2, her2, mln19, neu, ngl. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Synthetic. Organism_taxid: 32630.
2.55Å     R-factor:   0.203     R-free:   0.253
Authors: C.Jost,J.Schilling,A.Plueckthun
Key ref: C.Jost et al. (2013). Structural basis for eliciting a cytotoxic effect in HER2-overexpressing cancer cells via binding to the extracellular domain of HER2. Structure, 21, 1979-1991. PubMed id: 24095059 DOI: 10.1016/j.str.2013.08.020
28-Oct-12     Release date:   16-Oct-13    
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Protein chain
Pfam   ArchSchema ?
P04626  (ERBB2_HUMAN) -  Receptor tyrosine-protein kinase erbB-2
1255 a.a.
169 a.a.*
Protein chain
No UniProt id for this chain
Struc: 162 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)


DOI no: 10.1016/j.str.2013.08.020 Structure 21:1979-1991 (2013)
PubMed id: 24095059  
Structural basis for eliciting a cytotoxic effect in HER2-overexpressing cancer cells via binding to the extracellular domain of HER2.
C.Jost, J.Schilling, R.Tamaskovic, M.Schwill, A.Honegger, A.Plückthun.
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.