5L0Q

Crystal structure of the complex between ADAM10 D+C domain and a conformation specific mAb 8C7.

Summary for 5L0Q

• Entry DOI: 10.2210/pdb5l0q/pdb
• Descriptor: Disintegrin and metalloproteinase domain-containing protein 10, mAb 8C7 light chain, mAb 8C7 heavy chain, ... (7 entities in total)
• Functional Keywords: adam protease, mab, 8c7, notch signaling, therapeutic antibody, cancer stem cell, drug resistance, hydrolase-immune system complex, hydrolase/immune system
• Biological source: Bos taurus (Bovine); More
• Total number of polymer chains: 6
• Total formula weight: 141029.31

Authors

Xu, K.,Saha, N.,Nikolov, D.B. (deposition date: 2016-07-28, release date: 2016-11-09, Last modification date: 2024-11-20)

Primary citation

Atapattu, L.,Saha, N.,Chheang, C.,Eissman, M.F.,Xu, K.,Vail, M.E.,Hii, L.,Llerena, C.,Liu, Z.,Horvay, K.,Abud, H.E.,Kusebauch, U.,Moritz, R.L.,Ding, B.S.,Cao, Z.,Rafii, S.,Ernst, M.,Scott, A.M.,Nikolov, D.B.,Lackmann, M.,Janes, P.W.
An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth.
J.Exp.Med., 213:1741-1757, 2016

PubMed Abstract: The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance.

PubMed: 27503072
DOI: 10.1084/jem.20151095

Experimental method

X-RAY DIFFRACTION (2.759 Å)