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PDBsum entry 6ht9
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Contents |
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202 a.a.
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316 a.a.
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297 a.a.
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References listed in PDB file
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Key reference
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Title
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Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition.
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Authors
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A.Cuppari,
H.Körschgen,
D.Fahrenkamp,
C.Schmitz,
T.Guevara,
K.Karmilin,
M.Kuske,
M.Olf,
E.Dietzel,
I.Yiallouros,
D.De sanctis,
T.Goulas,
R.Weiskirchen,
W.Jahnen-Dechent,
J.Floehr,
W.Stoecker,
L.Jovine,
F.X.Gomis-Rüth.
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Ref.
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IUCrJ, 2019,
6,
317-330.
[DOI no: ]
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PubMed id
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Abstract
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Mammalian fetuin-A and fetuin-B are abundant serum proteins with pleiotropic
functions. Fetuin-B is a highly selective and potent inhibitor of
metallo-peptidases (MPs) of the astacin family, which includes ovastacin in
mammals. By inhibiting ovastacin, fetuin-B is essential for female fertility.
The crystal structure of fetuin-B was determined unbound and in complex with
archetypal astacin, and it was found that the inhibitor has tandem cystatin-type
modules (CY1 and CY2). They are connected by an exposed linker with a rigid,
disulfide-linked 'CPDCP-trunk', and are followed by a C-terminal region (CTR)
with little regular secondary structure. The CPDCP-trunk and a hairpin of CY2
form a bipartite wedge, which slots into the active-site cleft of the MP. These
elements occupy the nonprimed and primed sides of the cleft, respectively, but
spare the specificity pocket so that the inhibitor is not cleaved. The aspartate
in the trunk blocks the catalytic zinc of astacin, while the CY2 hairpin binds
through a QWVXGP motif. The CY1 module assists in structural integrity
and the CTR is not involved in inhibition, as verified by in vitro
studies using a cohort of mutants and variants. Overall, the inhibition conforms
to a novel 'raised-elephant-trunk' mechanism for MPs, which is reminiscent of
single-domain cystatins that target cysteine peptidases. Over 200 sequences from
vertebrates have been annotated as fetuin-B, underpinning its ubiquity and
physiological relevance; accordingly, sequences with conserved CPDCP- and
QWVXGP-derived motifs have been found from mammals to cartilaginous
fishes. Thus, the raised-elephant-trunk mechanism is likely to be generally
valid for the inhibition of astacins by orthologs of fetuin-B.
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