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92 a.a.
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492 a.a.
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214 a.a.
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221 a.a.
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* Residue conservation analysis
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PDB id:
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Hydrolase/immune system
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Title:
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Crystal structure of pcsk9 in complex with fab from ldlr competitive antibody
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Structure:
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Proprotein convertase subtilisin/kexin type 9. Chain: a. Fragment: unp residues 31-152. Synonym: proprotein convertase pc9, subtilisin/kexin-like protease pc9, neural apoptosis-regulated convertase 1, narc-1. Engineered: yes. Proprotein convertase subtilisin/kexin type 9. Chain: b. Fragment: unp residues 153-692.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: narc1, pcsk9, psec0052. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: hi-five. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.30Å
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R-factor:
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0.191
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R-free:
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0.209
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Authors:
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D.E.Piper,N.P.C.Walker,W.G.Romanow,S.T.Thibault,M.M.Tsai,E.Yang
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Key ref:
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J.C.Chan
et al.
(2009).
A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.
Proc Natl Acad Sci U S A,
106,
9820-9825.
PubMed id:
DOI:
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Date:
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17-Apr-09
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Release date:
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05-May-09
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PROCHECK
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Headers
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References
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Q8NBP7
(PCSK9_HUMAN) -
Proprotein convertase subtilisin/kexin type 9 from Homo sapiens
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Seq:
Struc:
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692 a.a.
92 a.a.
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Q8NBP7
(PCSK9_HUMAN) -
Proprotein convertase subtilisin/kexin type 9 from Homo sapiens
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Seq:
Struc:
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692 a.a.
492 a.a.*
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DOI no:
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Proc Natl Acad Sci U S A
106:9820-9825
(2009)
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PubMed id:
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A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.
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J.C.Chan,
D.E.Piper,
Q.Cao,
D.Liu,
C.King,
W.Wang,
J.Tang,
Q.Liu,
J.Higbee,
Z.Xia,
Y.Di,
S.Shetterly,
Z.Arimura,
H.Salomonis,
W.G.Romanow,
S.T.Thibault,
R.Zhang,
P.Cao,
X.P.Yang,
T.Yu,
M.Lu,
M.W.Retter,
G.Kwon,
K.Henne,
O.Pan,
M.M.Tsai,
B.Fuchslocher,
E.Yang,
L.Zhou,
K.J.Lee,
M.Daris,
J.Sheng,
Y.Wang,
W.D.Shen,
W.C.Yeh,
M.Emery,
N.P.Walker,
B.Shan,
M.Schwarz,
S.M.Jackson.
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ABSTRACT
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL
cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an
attractive therapeutic target for LDL-C lowering. We have generated a
neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9
adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits
PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR
protein levels, thereby increasing LDL uptake. A combination of mAb1 with a
statin increases LDLR levels in HepG2 cells more than either treatment alone. In
wild-type mice, mAb1 increases hepatic LDLR protein levels approximately 2-fold
and lowers total serum cholesterol by up to 36%: this effect is not observed in
LDLR(-/-) mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum
LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude
that anti-PCSK9 antibodies may be effective therapeutics for treating
hypercholesterolemia.
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Selected figure(s)
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Figure 2.
Structure of the PCSK9:Fab1 complex. (A) Fab1 binds to PCSK9
at the catalytic site and interacts with residues from both the
prodomain and catalytic domain. The binding of Fab1 to PCSK9
buries 2307 Å^2 total surface area. (B) Superposition of
the PCSK9:Fab1 complex (pink and magenta) and the PCSK9:EGF-AB
complex (11) (light cyan and cyan). Fab1 overlaps with the
C-terminal side of the EGF-A domain from the LDLR.
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Figure 4.
Changes in serum LDL-C after i.v. administration of mAb1 to
cynomolgus monkeys. A single injection of mAb1 led to (A) a
significant lowering of serum TC, observed as early as 8 h after
administration of mAb1; (B) a significant lowering in serum
LDL-C, with maximal lowering observed at 10 days after
injection; and (C) a significant lowering of HDL-C at day 3 and
day 7. Results are expressed as mean ± SEM. *P < 0.05;
**P < 0.01; ***P < 0.001 vs. anti-KLH control antibody at the
same time point, n = 4 per group. (D) Temporal relationship
between free circulating PCSK9 levels and serum LDL-C after
administration of mAb1.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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N.G.Seidah,
and
A.Prat
(2012).
The biology and therapeutic targeting of the proprotein convertases.
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Nat Rev Drug Discov,
11,
367-383.
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A.Brautbar,
and
C.M.Ballantyne
(2011).
Pharmacological strategies for lowering LDL cholesterol: statins and beyond.
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Nat Rev Cardiol,
8,
253-265.
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N.G.Seidah
(2011).
What lies ahead for the proprotein convertases?
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Ann N Y Acad Sci,
1220,
149-161.
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R.C.Bauer,
I.M.Stylianou,
and
D.J.Rader
(2011).
Functional validation of new pathways in lipoprotein metabolism identified by human genetics.
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Curr Opin Lipidol,
22,
123-128.
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R.J.Konrad,
J.S.Troutt,
and
G.Cao
(2011).
Effects of currently prescribed LDL-C-lowering drugs on PCSK9 and implications for the next generation of LDL-C-lowering agents.
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Lipids Health Dis,
10,
38.
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D.C.Chan,
S.J.Hamilton,
K.A.Rye,
G.T.Chew,
A.J.Jenkins,
G.Lambert,
and
G.F.Watts
(2010).
Fenofibrate concomitantly decreases serum proprotein convertase subtilisin/kexin type 9 and very-low-density lipoprotein particle concentrations in statin-treated type 2 diabetic patients.
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Diabetes Obes Metab,
12,
752-756.
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G.Dubuc,
M.Tremblay,
G.Paré,
H.Jacques,
J.Hamelin,
S.Benjannet,
L.Boulet,
J.Genest,
L.Bernier,
N.G.Seidah,
and
J.Davignon
(2010).
A new method for measurement of total plasma PCSK9: clinical applications.
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J Lipid Res,
51,
140-149.
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J.Davignon,
G.Dubuc,
and
N.G.Seidah
(2010).
The influence of PCSK9 polymorphisms on serum low-density lipoprotein cholesterol and risk of atherosclerosis.
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Curr Atheroscler Rep,
12,
308-315.
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J.S.Troutt,
W.E.Alborn,
G.Cao,
and
R.J.Konrad
(2010).
Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels.
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J Lipid Res,
51,
345-351.
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L.Trapani,
and
V.Pallottini
(2010).
Age-Related Hypercholesterolemia and HMG-CoA Reductase Dysregulation: Sex Does Matter (A Gender Perspective).
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Curr Gerontol Geriatr Res,
(),
420139.
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N.Gupta,
N.Fisker,
M.C.Asselin,
M.Lindholm,
C.Rosenbohm,
H.Ørum,
J.Elmén,
N.G.Seidah,
and
E.M.Straarup
(2010).
A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo.
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PLoS One,
5,
e10682.
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P.Costet
(2010).
Molecular pathways and agents for lowering LDL-cholesterol in addition to statins.
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Pharmacol Ther,
126,
263-278.
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S.M.Paul,
D.S.Mytelka,
C.T.Dunwiddie,
C.C.Persinger,
B.H.Munos,
S.R.Lindborg,
and
A.L.Schacht
(2010).
How to improve R&D productivity: the pharmaceutical industry's grand challenge.
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Nat Rev Drug Discov,
9,
203-214.
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D.Lindholm,
B.C.Bornhauser,
and
L.Korhonen
(2009).
Mylip makes an Idol turn into regulation of LDL receptor.
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Cell Mol Life Sci,
66,
3399-3402.
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D.Steinberg,
and
J.L.Witztum
(2009).
Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels.
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Proc Natl Acad Sci U S A,
106,
9546-9547.
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S.Poirier,
G.Mayer,
V.Poupon,
P.S.McPherson,
R.Desjardins,
K.Ly,
M.C.Asselin,
R.Day,
F.J.Duclos,
M.Witmer,
R.Parker,
A.Prat,
and
N.G.Seidah
(2009).
Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route.
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J Biol Chem,
284,
28856-28864.
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,
(0).
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,
(),
0.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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Links
