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PDBsum entry 3zl7
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References listed in PDB file
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Key reference
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Title
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Mapping the conformational space accessible to bace2 using surface mutants and cocrystals with FAB fragments, Fynomers and xaperones.
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Authors
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D.W.Banner,
B.Gsell,
J.Benz,
J.Bertschinger,
D.Burger,
S.Brack,
S.Cuppuleri,
M.Debulpaep,
A.Gast,
D.Grabulovski,
M.Hennig,
H.Hilpert,
W.Huber,
A.Kuglstatter,
E.Kusznir,
T.Laeremans,
H.Matile,
C.Miscenic,
A.C.Rufer,
D.Schlatter,
J.Steyaert,
M.Stihle,
R.Thoma,
M.Weber,
A.Ruf.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2013,
69,
1124-1137.
[DOI no: ]
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PubMed id
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Abstract
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The aspartic protease BACE2 is responsible for the shedding of the transmembrane
protein Tmem27 from the surface of pancreatic β-cells, which leads to
inactivation of the β-cell proliferating activity of Tmem27. This role of BACE2
in the control of β-cell maintenance suggests BACE2 as a drug target for
diabetes. Inhibition of BACE2 has recently been shown to lead to improved
control of glucose homeostasis and to increased insulin levels in
insulin-resistant mice. BACE2 has 52% sequence identity to the well studied
Alzheimer's disease target enzyme β-secretase (BACE1). High-resolution BACE2
structures would contribute significantly to the investigation of this enzyme as
either a drug target or anti-target. Surface mutagenesis, BACE2-binding antibody
Fab fragments, single-domain camelid antibody VHH fragments (Xaperones) and
Fyn-kinase-derived SH3 domains (Fynomers) were used as crystallization helpers
to obtain the first high-resolution structures of BACE2. Eight crystal
structures in six different packing environments define an ensemble of
low-energy conformations available to the enzyme. Here, the different strategies
used for raising and selecting BACE2 binders for cocrystallization are described
and the crystallization success, crystal quality and the time and resources
needed to obtain suitable crystals are compared.
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