PDBsum entry 6oge

Transferase/immune system

PDB id: 6oge

Contents

Protein chains

619 a.a.

214 a.a.

222 a.a.

214 a.a.

220 a.a.

Ligands

NAG-NAG-BMA-MAN

NAG ×5

PDB id:

6oge

Name:

Transferase/immune system

Title:

Cryo-em structure of her2 extracellular domain-trastuzumab fab- pertuzumab fab complex

Structure:

Receptor tyrosine-protein kinase erbb-2. Chain: a. 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. Pertuzumab fab light chain. Chain: b. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: erbb2, her2, mln19, neu, ngl. Expressed in: homo sapiens. Expression_system_taxid: 9606. Gene: igkc. Expressed in: cricetulus griseus. Expression_system_taxid: 10029.

Authors:

Y.Hao,X.Yu,Y.Bai,X.Huang

Key ref:

Y.Hao et al. (2019). Cryo-EM Structure of HER2-trastuzumab-pertuzumab complex. PLoS One, 14, e0216095. PubMed id: 31042744 DOI: 10.1371/journal.pone.0216095

Date:

02-Apr-19 Release date: 15-May-19

Protein chain

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

Seq: 1255 a.a.

Struc: 619 a.a.

Protein chain

P01834  (IGKC_HUMAN) -  Immunoglobulin kappa constant from Homo sapiens

Seq: 107 a.a.

Struc: 214 a.a.

Protein chain

P0DOX5  (IGG1_HUMAN) -  Immunoglobulin gamma-1 heavy chain from Homo sapiens

Seq: 449 a.a.

Struc: 222 a.a.*

Protein chain

P01834  (IGKC_HUMAN) -  Immunoglobulin kappa constant from Homo sapiens

Seq: 107 a.a.

Struc: 214 a.a.

Protein chain

Q6GMX6  (Q6GMX6_HUMAN) -  IGH@ protein from Homo sapiens

Seq: 465 a.a.

Struc: 220 a.a.*

* PDB and UniProt seqs differ at 89 residue positions (black crosses)

Enzyme reactions

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

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = NAG) matches with 41.38% similarity) + ADP + H(+)

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

Added reference

DOI no: 10.1371/journal.pone.0216095

PLoS One 14:e0216095 (2019)

PubMed id: 31042744

Cryo-EM Structure of HER2-trastuzumab-pertuzumab complex.

Y.Hao, X.Yu, Y.Bai, H.J.McBride, X.Huang.

ABSTRACT

Trastuzumab and pertuzumab are monoclonal antibodies that bind to distinct subdomains of the extracellular domain of human epidermal growth factor receptor 2 (HER2). Adding these monoclonal antibodies to the treatment regimen of HER2-positive breast cancer has changed the paradigm for treatment in that form of cancer. Synergistic activity has been observed with the combination of these two antibodies leading to hypotheses regarding the mechanism(s) and to the development of bispecific antibodies to maximize the clinical effect further. Although the individual crystal structures of HER2-trastuzumab and HER2-pertuzumab revealed the distinct binding sites and provided the structural basis for their anti-tumor activities, detailed structural information on the HER2-trastuzumab-pertuzumab complex has been elusive. Here we present the cryo-EM structure of HER2-trastuzumab-pertuzumab at 4.36 Å resolution. Comparison with the binary complexes reveals no cooperative interaction between trastuzumab and pertuzumab, and provides key insights into the design of novel, high-avidity bispecific molecules with potentially greater clinical efficacy.