9pi9
Sacituzumab Fab bound to Trop2 Dimer
Structural highlights
DiseaseTACD2_HUMAN Honey-droplet corneal dystrophy;Gelatinous drop-like corneal dystrophy. The disease is caused by mutations affecting the gene represented in this entry. FunctionTACD2_HUMAN May function as a growth factor receptor. Publication Abstract from PubMedSacituzumab govitecan (SG) is a therapeutic antibody-drug conjugate globally approved for the treatment of breast cancer. SG targets the trophoblast cell-surface antigen-2 (Trop2) at the surface of cancer cells to deliver the cytotoxic topoisomerase I inhibitor SN-38 to the tumor microenvironment. SN-38 is covalently linked to the humanized monoclonal antibody (mAb) sacituzumab via a hydrolyzable linker. Here, we describe the 1.56-A X-ray crystal structure and stoichiometry of the human Trop2 ectodomain in complex with a sacituzumab (hRS7) antigen-binding Fab fragment. The complex reveals a 2:2 stoichiometry where two sacituzumab Fabs bind across the two Trop2 dimer subunits, inducing a conformational change compared to the apo-structure. Cryo-electron microscopy (cryoEM) and size-exclusion chromatography in combination with multi-angle light scattering (SEC-MALS) analysis of the intact sacituzumab mAb bound to the Trop2 ECD reveals a complex whereby sacituzumab engages two Trop2 dimers in a 2:4 stoichiometry. The therapeutic antibody sacituzumab induces trophoblast cell-surface antigen-2 conformational rearrangement.,Ferrao R, Zhang J, Chou CC, Nieto A, Langeslay D, Chatterjee M, Jin D, Hung M, Scott I, Nagel M, Xing W, Letarte S, Wang J, Ambrogelly A, Lansdon EB Structure. 2025 Nov 27:S0969-2126(25)00437-X. doi: 10.1016/j.str.2025.11.002. PMID:41314216[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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