PDBsum entry 4hrm

Transferase/de novo protein

PDB id: 4hrm

Contents

Protein chains

166 a.a.

139 a.a.

123 a.a.

119 a.a.

PDB id:

4hrm

Name:

Transferase/de novo protein

Title:

Structural basis for eliciting a cytotoxic effect in her2- overexpressing cancer cells via binding to the extracellular domain of her2

Structure:

Domain i of receptor tyrosine-protein kinase erbb-2. Chain: c, a. Fragment: n-terminal extracellular domain i, unp residues 24-219. Synonym: metastatic lymph node gene 19 protein, mln 19, proto- oncogene neu, proto-oncogenE C-erbb-2, tyrosine kinase-type cell surface receptor her2, p185erbb2. Engineered: yes. Mutation: yes. Designed ankyrin repeat protein 9_26.

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.

Resolution:

3.20Å R-factor: 0.315 R-free: 0.339

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

Date:

28-Oct-12 Release date: 16-Oct-13

Protein chain

P04626  (ERBB2_HUMAN) -  Receptor tyrosine-protein kinase erbB-2 from Homo sapiens

Seq: 1255 a.a.

Struc: 166 a.a.*

Protein chain

P04626  (ERBB2_HUMAN) -  Receptor tyrosine-protein kinase erbB-2 from Homo sapiens

Seq: 1255 a.a.

Struc: 139 a.a.*

Protein chain

No UniProt id for this chain

Struc: 123 a.a.

Protein chain

No UniProt id for this chain

Struc: 119 a.a.

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains C, A: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

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.

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.