| Title | Structure basis for AA98 inhibition on the activation of endothelial cells mediated by CD146 |
| Authors | Chen, Xuehui Yan, Huiwen Liu, Dan Xu, Qingji Duan, Hongxia Feng, Jing Yan, Xiyun Xie, Can |
| Affiliation | Chinese Acad Sci, Inst Biophys, Key Lab Prot & Peptide Pharmaceut, Beijing 100101, Peoples R China Peking Univ, Sch Life Sci, State Key Lab Membrane Biol, Lab Mol Biophys, Beijing 100871, Peoples R China Chinese Acad Sci, Inst Biophys, Key Lab RNA Biol, Beijing 100101, Peoples R China Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China Chinese Acad Sci, Hefei Inst Phys Sci, High Magnet Field Lab, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Anhui, Peoples R China Int Magnetobiol Frontier Res Ctr, Sci Isl, Hefei 230031, Peoples R China |
| Keywords | ADHESION MOLECULE MONOCLONAL-ANTIBODY HUMAN-MELANOMA MCAM DIMERIZATION MUC18 RECEPTOR PROTEIN CANCER ANGIOGENESIS |
| Issue Date | 21-May-2021 |
| Publisher | ISCIENCE |
| Abstract | CD146 is an adhesion molecule that plays important roles in angiogenesis, cancer metastasis, and immune response. It exists as a monomer or dimer on the cell surface. AA98 is a monoclonal antibody that binds to CD146, which abrogates the activation of CD146-mediated signaling pathways and shows inhibitory effects on tumor growth. However, how AA98 inhibits the function of CD146 remains unclear. Here, we describe a crystal structure of the CD146/AA98 Fab complex at a resolution of 2.8 angstrom. Monomeric CD146 is stabilized by AA98 Fab binding to the junction region of CD146 domains 4 and 5. A higher-affinity AA98 variant (here named HA98) was thus rationally designed. Better binding to CD146 and prominent inhibition on cell migration were achieved with HA98. Further experiments on xenografted melanoma in mice with HA98 revealed superior inhibitory effects on tumor growth to those of AA98, which suggested future applications of this antibody in cancer therapy. |
| URI | http://hdl.handle.net/20.500.11897/615321 |
| DOI | 10.1016/j.isci.2021.102417 |
| Indexed | SCI(E) |
| Appears in Collections: | 生命科学学院 膜生物学国家重点实验室 |
