3WLW

Molecular Architecture of the ErbB2 Extracellular Domain Homodimer

Summary for 3WLW

• Entry DOI: 10.2210/pdb3wlw/pdb
• Related: 3WN3
• Descriptor: Receptor tyrosine-protein kinase erbB-2, Antibody H Chain, Antibody L Chain, ... (6 entities in total)
• Functional Keywords: hydrolase-immune system complex, hydrolase/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 217494.90

Authors

Hu, S.,Lou, Z.Y.,Guo, Y.J. (deposition date: 2013-11-15, release date: 2015-05-27, Last modification date: 2024-11-13)

Primary citation

Hu, S.,Sun, Y.,Meng, Y.,Wang, X.,Yang, W.,Fu, W.,Guo, H.,Qian, W.,Hou, S.,Li, B.,Rao, Z.,Lou, Z.,Guo, Y.
Molecular architecture of the ErbB2 extracellular domain homodimer.
Oncotarget, 6:1695-1706, 2015

PubMed Abstract: Human epidermal growth factor receptors (HERs or ErbBs) play crucial roles in numerous cellular processes. ErbB2 is a key member of ErbB family, and its overexpression is recognized as a frequent molecular abnormality. In cancer, this overexpression correlates with aggressive disease and poor patient outcomes. Dimer-dependent phosphorylation is a key event for the signal transduction of ErbBs. However, the molecular mechanism of the dimerization of ErbB2 remains elusive. In the present work, we report the homodimer architecture of the ErbB2 extracellular domain (ECD) which is unique compared with other dimer-models of ErbBs. The structure of the ErbB2 ECD homodimer represents a "back to head" interaction, in which a protruding β-hairpin arm in domain II of one ErbB2 protomer is inserted into a C-shaped pocket created by domains I-III of the adjacent ErbB2 protomer. This dimerized architecture and its impact on the phosphorylation of ErbB2 intracellular domain were further verified by a mutagenesis study. We also elucidated the different impacts of two clinically administered therapeutic antibodies, trastuzumab and pertuzumab, on ErbB2 dimerization. This information not only provides an understanding of the molecular mechanism of ErbBs dimerization but also elucidates ErbB2-targeted therapy at the molecular level.

PubMed: 25633808
DOI: 10.18632/oncotarget.2713

Experimental method

X-RAY DIFFRACTION (3.088 Å)