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PDBsum entry 5l0q
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Hydrolase/immune system
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PDB id
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5l0q
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Contents |
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203 a.a.
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212 a.a.
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213 a.a.
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PDB id:
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| Name: |
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Hydrolase/immune system
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Title:
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Crystal structure of the complex between adam10 d+c domain and a conformation specific mab 8c7.
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Structure:
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Disintegrin and metalloproteinase domain-containing protein 10. Chain: a, d. Fragment: unp residues 455-646. Synonym: adam 10,kuzbanian protein homolog,mammalian disintegrin- metalloprotease,myelin-associated metalloproteinase. Engineered: yes. Mab 8c7 light chain. Chain: b, e.
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Source:
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Bos taurus. Bovine. Organism_taxid: 9913. Gene: adam10, madm. Expressed in: homo sapiens. Expression_system_taxid: 9606. Homo sapiens. Organism_taxid: 9606. Expression_system_taxid: 9606
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Resolution:
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2.76Å
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R-factor:
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0.205
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R-free:
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0.251
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Authors:
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K.Xu,N.Saha,D.B.Nikolov
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Key ref:
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L.Atapattu
et al.
(2016).
An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth.
J Exp Med,
213,
1741-1757.
PubMed id:
DOI:
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Date:
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28-Jul-16
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Release date:
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09-Nov-16
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PROCHECK
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Headers
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References
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Q10741
(ADA10_BOVIN) -
Disintegrin and metalloproteinase domain-containing protein 10 from Bos taurus
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Seq:
Struc:
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748 a.a.
203 a.a.*
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Enzyme class:
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Chains A, D:
E.C.3.4.24.81
- ADAM10 endopeptidase.
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Cofactor:
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Zn(2+)
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DOI no:
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J Exp Med
213:1741-1757
(2016)
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PubMed id:
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An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth.
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L.Atapattu,
N.Saha,
C.Chheang,
M.F.Eissman,
K.Xu,
M.E.Vail,
L.Hii,
C.Llerena,
Z.Liu,
K.Horvay,
H.E.Abud,
U.Kusebauch,
R.L.Moritz,
B.S.Ding,
Z.Cao,
S.Rafii,
M.Ernst,
A.M.Scott,
D.B.Nikolov,
M.Lackmann,
P.W.Janes.
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ABSTRACT
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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.
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Links
