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PDBsum entry 4ogx
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Hydrolase/antibody
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PDB id
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4ogx
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Contents |
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236 a.a.
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216 a.a.
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212 a.a.
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PDB id:
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| Name: |
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Hydrolase/antibody
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Title:
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Crystal structure of fab dx-2930 in complex with human plasma kallikrein at 2.4 angstrom resolution
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Structure:
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Plasma kallikrein. Chain: a. Fragment: unp residues 391-631. Synonym: fletcher factor, kininogenin, plasma prekallikrein, plasma kallikrein heavy chain, plasma kallikrein light chain. Engineered: yes. Mutation: yes. Dx-2930 heavy chain. Chain: h.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: klk3, klkb1, klkb1_human. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.40Å
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R-factor:
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0.188
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R-free:
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0.236
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Authors:
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T.E.Edwards,M.C.Clifton,J.Abendroth,A.Nixon,R.Ladner
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Key ref:
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J.A.Kenniston
et al.
(2014).
Inhibition of plasma kallikrein by a highly specific active site blocking antibody.
J Biol Chem,
289,
23596-23608.
PubMed id:
DOI:
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Date:
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16-Jan-14
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Release date:
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09-Jul-14
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PROCHECK
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Headers
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References
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P03952
(KLKB1_HUMAN) -
Plasma kallikrein from Homo sapiens
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Seq:
Struc:
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638 a.a.
236 a.a.*
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Enzyme class:
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Chain A:
E.C.3.4.21.34
- plasma kallikrein.
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Reaction:
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Cleaves selectively Arg-|-Xaa and Lys-|-Xaa bonds, including Lys-|-Arg and Arg-|-Ser bonds in (human) kininogen to release bradykinin.
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DOI no:
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J Biol Chem
289:23596-23608
(2014)
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PubMed id:
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Inhibition of plasma kallikrein by a highly specific active site blocking antibody.
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J.A.Kenniston,
R.R.Faucette,
D.Martik,
S.R.Comeau,
A.P.Lindberg,
K.J.Kopacz,
G.P.Conley,
J.Chen,
M.Viswanathan,
N.Kastrapeli,
J.Cosic,
S.Mason,
M.DiLeo,
J.Abendroth,
P.Kuzmic,
R.C.Ladner,
T.E.Edwards,
C.TenHoor,
B.A.Adelman,
A.E.Nixon,
D.J.Sexton.
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ABSTRACT
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Plasma kallikrein (pKal) proteolytically cleaves high molecular weight kininogen
to generate the potent vasodilator and the pro-inflammatory peptide, bradykinin.
pKal activity is tightly regulated in healthy individuals by the serpin
C1-inhibitor, but individuals with hereditary angioedema (HAE) are deficient in
C1-inhibitor and consequently exhibit excessive bradykinin generation that in
turn causes debilitating and potentially fatal swelling attacks. To develop a
potential therapeutic agent for HAE and other pKal-mediated disorders, we used
phage display to discover a fully human IgG1 monoclonal antibody (DX-2930)
against pKal. In vitro experiments demonstrated that DX-2930 potently inhibits
active pKal (Ki = 0.120 ± 0.005 nm) but does not target either the zymogen
(prekallikrein) or any other serine protease tested. These findings are
supported by a 2.1-Å resolution crystal structure of pKal complexed to a
DX-2930 Fab construct, which establishes that the pKal active site is fully
occluded by the antibody. DX-2930 injected subcutaneously into cynomolgus
monkeys exhibited a long half-life (t½ ∼12.5 days) and blocked high molecular
weight kininogen proteolysis in activated plasma in a dose- and time-dependent
manner. Furthermore, subcutaneous DX-2930 reduced carrageenan-induced paw edema
in rats. A potent and long acting inhibitor of pKal activity could be an
effective treatment option for pKal-mediated diseases, such as HAE.
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