期刊
ISCIENCE
卷 24, 期 10, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2021.103190
关键词
-
资金
- National Major Science & Technology Major Project [2018ZX10302302-001-002, 2018ZX10101004-001-003]
- Strategic Priority Research Program of Chinese Academy of Sciences (CAS) [XDB29040201]
- Chair Professor Grant (CPG) [2019-00019-FHS]
The crystal structures of TROP-2-ECD show that TROP-2 can form either cis or trans dimers, and can assemble into tetramers through distinct interfaces. Sacituzumab binds to a stretched polypeptide in the CPD region of TROP-2, which is not involved in cis- or trans-interactions. These findings provide insights into the molecular assembly of TROP-2 on tumor cells and potential implications for the design of biologics for tumor therapy.
Human 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 either cis-or trans-dimers depending on which distinct but overlapping interfaces is used to engage with monomers. The cis-or trans-tetrameric forms of TROP-2 can also be assembled with a non-overlapping interface with either cis- or trans-dimeriza-tion, suggesting that cis- and trans-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 either cis-or trans -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.
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