9z2h

Crystal structure of A10 Fab in complex with the EGFR peptide

spinqualitylabelsall models 9z2h, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9z2h is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.45Å Ligands: ACT Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease EGFR_HUMAN Defects in EGFR are associated with lung cancer (LNCR) [MIM:211980. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. Function EGFR_HUMAN Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin. Isoform 2 may act as an antagonist of EGF action. Publication Abstract from PubMed The humanization of mouse monoclonal antibodies targeting tumor antigens allows for the safe and repeated administration of therapeutic antibodies to humans. Previously, we reported on mouse monoclonal antibody 40H3 and its reactivity with a conformational epitope exposed on EGFR when expressed by cancer cells. To advance 40H3 toward the clinic, we generated various humanized variants, evaluated each for binding to either the peptide epitope or intact cells, and now report on the lead candidate, A10, which exhibited the strongest cell binding activity. A10 binding was characterized in detail on a collection of cancer cell lines each harboring different EGFR mutations or overexpressed EGFR and, where appropriate, compared with 40H3 or Cetuximab. A structural study of the A10 Fab with bound peptide revealed that A10 was unlikely to react with either tethered or untethered forms of wild type EGFR, as the accessibility to the peptide epitope by A10 is EGFR conformational dependent. As a proof of concept to produce therapeutic agents from A10, an antibody drug conjugate (ADC) with monomethyl-auristatin-E (MMAE) was generated and proved potently cytotoxic for cells displaying high levels of EGFR. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-46245-y. Targeting cancer expressed EGFR with a humanized monoclonal antibody.,Costa TGF, Sarnovsky R, Zhan J, Maslanka CA, Obiorah I, Xia D, FitzGerald D, Antignani A Sci Rep. 2026 Mar 28;16(1):10814. doi: 10.1038/s41598-026-46245-y. PMID:41904250 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA