摘要：SummaryHuman trophoblast cell surface antigen 2 (TROP-2) is an important target of tumor therapy, and antibody-drug conjugates with sacituzumab targeting TROP-2 have been approved for the treatment of triple-negative breast cancer. Here, we report the crystal structures of TROP-2-ECD, which can be eithercis-ortrans-dimers depending on which distinct but overlapping interfaces is used to engage with monomers. Thecis-ortrans-tetrameric forms of TROP-2 can also be assembled with a non-overlapping interface with eithercis- ortrans-dimerization, suggesting thatcis- andtrans-dimers cluster on the cell surface. The binding site of sacituzumab on TROP-2 is mapped to be located on a stretched polypeptide in CPD (Q237-Q252), which is not involved in eithercis-ortrans-interactions. The present findings will improve understanding of the molecular assembly of TROP-2 on tumor cells and shed light on future design of biologics for tumor therapy.Graphical abstractDisplay OmittedHighlights•TROP-2-ECD assembles intocis- ortrans-dimer•cis-ortrans-dimeric TROP-2-ECD can be further cross-linked•Sacituzumab binds to the stretched polypeptide in CPD not involved in TROP-2 assemblyImmunology; Structural biology; Cancer
