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PDBsum entry 1koe
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Angiogenesis inhibitor
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PDB id
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1koe
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the angiogenesis inhibitor endostatin at 1.5 a resolution.
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Authors
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E.Hohenester,
T.Sasaki,
B.R.Olsen,
R.Timpl.
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Ref.
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EMBO J, 1998,
17,
1656-1664.
[DOI no: ]
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PubMed id
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Abstract
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A number of extracellular proteins contain cryptic inhibitors of angiogenesis.
Endostatin is a 20 kDa C-terminal proteolytic fragment of collagen XVIII that
potently inhibits endothelial cell proliferation and angiogenesis. Therapy of
experimental cancer with endostatin leads to tumour dormancy and does not induce
resistance. We have expressed recombinant mouse endostatin and determined its
crystal structure at 1.5 A resolution. The structure reveals a compact fold
distantly related to the C-type lectin carbohydrate recognition domain and the
hyaluronan-binding Link module. The high affinity of endostatin for heparin is
explained by the presence of an extensive basic patch formed by 11 arginine
residues. Endostatin may inhibit angiogenesis by binding to the heparan sulphate
proteoglycans involved in growth factor signalling.
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Figure 2.
Figure 2 Stereo view of the final 2F[obs]-F[calc] map at 1.5 Å
resolution. The region around  -strand
P is shown, with the disulphide bond between Cys164 and Cys304
in the centre. The map is contoured at the 1.5  level
and is shown with the refined model superimposed. The figure was
made with BOBSCRIPT (R.Esnouf, personal communication), a
modified version of MOLSCRIPT (Kraulis, 1991).
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Figure 5.
Figure 5 Electrostatic surface representation (Nicholls, 1992)
of endostatin. The two views of the endostatin surface are
related by a rotation of 130° about the horizontal axis. Blue
indicates regions of positive potential and red regions of
negative potential, at the 5 kT/e level. The N- and the
C-termini are indicated; basic residues and the solvent-exposed
side chains of Phe162 and Phe165 are labelled in yellow and
white, respectively. The hatched area corresponds to the
oligosaccharide-binding site of C-type lectin CRDs.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(1998,
17,
1656-1664)
copyright 1998.
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Secondary reference #1
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Title
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Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.
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Authors
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M.S.O'Reilly,
T.Boehm,
Y.Shing,
N.Fukai,
G.Vasios,
W.S.Lane,
E.Flynn,
J.R.Birkhead,
B.R.Olsen,
J.Folkman.
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Ref.
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Cell, 1997,
88,
277-285.
[DOI no: ]
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PubMed id
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Figure 2.
Figure 2. Purification of an Inhibitor of Endothelial
Proliferation from EOMA-Conditioned Media(A) SDS-PAGE. An
aliquot (  vert,
similar 100 ng) of the purified inhibitor of endothelial cell
proliferation was analyzed by electrophoresis in a 10%–18%
polyacrylamide gel. Inhibitory activity was associated with a
protein of apparent M[r] 20,000 (silver stain). Molecular mass
markers (× 10^−3) are as indicated.(B) Amino acid
sequence. The N-terminal sequence of the purified inhibitor of
endothelial cell proliferation (endostatin) is noted in relation
to a schematic of collagen XVIII. N-termi- nal sequence reveals
identity of the inhibitor to a 20 kDa C-terminal fragment (solid
shading) of collagen XVIII. We have named this inhibitor
endostatin. The open boxes represent the collagenous domains of
collagen XVIII.
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Figure 7.
Figure 7. Systemic Therapy with Recombinant Endostatin
Regresses a Wide Variety of Primary MalignanciesThe subcutaneous
dorsa of mice were implanted with Lewis lung carcinomas and
systemic therapy with recombinant mouse endostatin (20
mg/kg/day) was begun when tumors were vert,
similar 200 mm^3 (1% of body weight). Tumors in the mice treated
with endostatin rapidly regressed and were inhibited by >99%
relative to saline-treated controls (n = 5). Each point
represents mean ± SEM for ten (T241), four (B16F10), or
three (EOMA) mice.
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The above figures are
reproduced from the cited reference
with permission from Cell Press
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