6xsw
Structure of the Notch3 NRR in complex with an antibody Fab Fragment
Structural highlights
DiseaseNOTC3_HUMAN CADASIL;Infantile myofibromatosis. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionNOTC3_HUMAN Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Publication Abstract from PubMedAberrant NOTCH3 signaling and overexpression is oncogenic, associated with cancer stem cells and drug resistance, yet therapeutic targeting remains elusive. Here, we develop NOTCH3-targeted antibody drug conjugates (NOTCH3-ADCs) by bioconjugation of an auristatin microtubule inhibitor through a protease cleavable linker to two antibodies with differential abilities to inhibit signaling. The signaling inhibitory antibody rapidly induces ligand-independent receptor clustering and internalization through both caveolin and clathrin-mediated pathways. The non-inhibitory antibody also efficiently endocytoses via clathrin without inducing receptor clustering but with slower lysosomal co-localization kinetics. In addition, DLL4 ligand binding to the NOTCH3 receptor mediates transendocytosis of NOTCH3-ADCs into ligand-expressing cells. NOTCH3-ADCs internalize into receptor and ligand cells independent of signaling and induce cell death in both cell types representing an atypical mechanism of ADC cytotoxicity. Treatment of xenografts with NOTCH3-ADCs leads to sustained tumor regressions, outperforms standard-of-care chemotherapy, and allows targeting of tumors that overexpress NOTCH3 independent of signaling inhibition. NOTCH3-targeted antibody drug conjugates regress tumors by inducing apoptosis in receptor cells and through transendocytosis into ligand cells.,Geles KG, Gao Y, Giannakou A, Sridharan L, Yamin TT, Zhang J, Karim R, Bard J, Piche-Nicholas N, Charati M, Maderna A, Lucas J, Golas J, Guffroy M, Pirie-Shepherd S, Roy M, Qian J, Franks T, Zhong W, O'Donnell CJ, Tchistiakova L, Gerber HP, Sapra P Cell Rep Med. 2021 May 18;2(5):100279. doi: 10.1016/j.xcrm.2021.100279. , eCollection 2021 May 18. PMID:34095881[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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