| Structural highlights
Function
[EREG_HUMAN] Ligand of the EGF receptor/EGFR and ERBB4. May be a mediator of localized cell proliferation. As a mitogen it may stimulate cell proliferation and/or angiogenesis.[1]
Publication Abstract from PubMed
Epiregulin (EPR) is a ligand of the epidermal growth factor (EGF) family that upon binding to its epidermal growth factor receptor (EGFR) stimulates proliferative signaling, especially in colon cancer cells. Here, we describe the three-dimensional structure of the EPR antibody (the 9E5(Fab) fragment) in the presence and absence of EPR. Among the six complementarity-determining regions (CDRs), CDR1-3 in the light chain and CDR2 in the heavy chain predominantly recognize EPR. In particular, CDR3 in the heavy chain dramatically moves with cis-trans isomerization of Pro103. A molecular dynamics simulation and mutational analyses revealed that Arg40 in EPR is a key residue for the specific binding of 9E5 IgG. From ITC analysis, the dissociation constant is determined to be 6.5 nM. Surface plasmon resonance analysis revealed that the dissociation rate of 9E5 IgG is extremely slow. The superimposed structure of 9E5(Fab)-EPR on the known complex structure of EGF-EGFR showed that the 9E5(Fab) paratope overlaps with Domains I and III on the EGFR, which reveals that the 9E5(Fab)-EPR complex could not bind to the EGFR. The 9E5 antibody will also be useful in medicine as a neutralizing antibody specific for colon cancer.
Epiregulin Recognition Mechanisms by Anti-Epiregulin Antibody 9E5: Structural, Functional and Molecular Dynamics Simulation Analyses.,Kado Y, Mizohata E, Nagatoishi S, Iijima M, Shinoda K, Miyafusa T, Nakayama T, Yoshizumi T, Sugiyama A, Kawamura T, Lee YH, Matsumura H, Doi H, Fujitani H, Kodama T, Shibasaki Y, Tsumoto K, Inoue T J Biol Chem. 2015 Dec 1. pii: jbc.M115.656009. PMID:26627827[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Komurasaki T, Toyoda H, Uchida D, Morimoto S. Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4. Oncogene. 1997 Dec 4;15(23):2841-8. PMID:9419975 doi:http://dx.doi.org/10.1038/sj.onc.1201458
- ↑ Kado Y, Mizohata E, Nagatoishi S, Iijima M, Shinoda K, Miyafusa T, Nakayama T, Yoshizumi T, Sugiyama A, Kawamura T, Lee YH, Matsumura H, Doi H, Fujitani H, Kodama T, Shibasaki Y, Tsumoto K, Inoue T. Epiregulin Recognition Mechanisms by Anti-Epiregulin Antibody 9E5: Structural, Functional and Molecular Dynamics Simulation Analyses. J Biol Chem. 2015 Dec 1. pii: jbc.M115.656009. PMID:26627827 doi:http://dx.doi.org/10.1074/jbc.M115.656009
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