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PDBsum entry 1bio
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Serine protease
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PDB id
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1bio
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Contents |
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.21.46
- complement factor D.
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Reaction:
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Cleaves component factor B (Arg-|-Lys) when in complex with C3b or with cobra venom factor (CVF).
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DOI no:
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J Mol Biol
282:1061-1081
(1998)
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PubMed id:
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Structures of native and complexed complement factor D: implications of the atypical His57 conformation and self-inhibitory loop in the regulation of specific serine protease activity.
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H.Jing,
Y.S.Babu,
D.Moore,
J.M.Kilpatrick,
X.Y.Liu,
J.E.Volanakis,
S.V.Narayana.
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ABSTRACT
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Factor D is a serine protease essential for the activation of the alternative
pathway of complement. The structures of native factor D and a complex formed
with isatoic anhydride inhibitor were determined at resolution of 2.3 and 1.5 A,
respectively, in an isomorphous monoclinic crystal form containing one molecule
per asymmetric unit. The native structure was compared with structures
determined previously in a triclinic cell containing two molecules with
different active site conformations. The current structure shows greater
similarity with molecule B in the triclinic cell, suggesting that this may be
the dominant factor D conformation in solution. The major conformational
differences with molecule A in the triclinic cell are located in four regions,
three of which are close to the active site and include some of the residues
shown to be critical for factor D catalytic activity. The conformational
flexibility associated with these regions is proposed to provide a structural
basis for the previously proposed substrate-induced reversible conformational
changes in factor D. The high-resolution structure of the factor D/isatoic
anhydride complex reveals the binding mode of the mechanism-based inhibitor. The
higher specificity towards factor D over trypsin and thrombin is based on
hydrophobic interactions between the inhibitor benzyl ring and the aliphatic
side-chain of Arg218 that is salt bridged with Asp189 at the bottom of the
primary specificity (S1) pocket.Comparison of factor D structural variants with
other serine protease structures revealed the presence of a unique
"self-inhibitory loop". This loop (214-218) dictates the resting-state
conformation of factor D by (1) preventing His57 from adopting active tautomer
conformation, (2) preventing the P1 to P3 residues of the substrate from forming
anti-parallel beta-sheets with the non-specific substrate binding loop, and (3)
blocking the accessibility of Asp189 to the positive1y charged P1 residue of the
substrate. The conformational switch from resting-state to active-state can only
be induced by the single macromolecular substrate, C3b-bound factor B. This
self-inhibitory mechanism is highly correlated with the unique functional
properties of factor D, which include high specificity toward factor B, low
esterolytic activity toward synthetic substrates, and absence of regulation by
zymogen and serpin-like or other natural inhibitors in blood.
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Selected figure(s)
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Figure 2.
Figure 2. Stereo view of 2Fo
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Fc election density map (contoured at 1.0s) around the active site of (a) mFD, and
(b) FD/IA. The inhibitor density is colored in magenta. This Figure was prepared in O (Jones et al., 1991).
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Figure 8.
Figure 8. Detailed comparison
among mFD, FD/IA and FD/DCI.
The differences between FD/IA
and FD/DCI are shown in continu-
ous lines and the differences
between FD/IA FD/IA and mFD
are shown in broken lines.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1998,
282,
1061-1081)
copyright 1998.
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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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A.D.Vogt,
A.Bah,
and
E.Di Cera
(2010).
Evidence of the E*-E equilibrium from rapid kinetics of Na+ binding to activated protein C and factor Xa.
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J Phys Chem B,
114,
16125-16130.
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F.Forneris,
D.Ricklin,
J.Wu,
A.Tzekou,
R.S.Wallace,
J.D.Lambris,
and
P.Gros
(2010).
Structures of C3b in complex with factors B and D give insight into complement convertase formation.
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Science,
330,
1816-1820.
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PDB codes:
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Z.Chen,
L.A.Pelc,
and
E.Di Cera
(2010).
Crystal structure of prethrombin-1.
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Proc Natl Acad Sci U S A,
107,
19278-19283.
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PDB code:
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A.Bah,
C.J.Carrell,
Z.Chen,
P.S.Gandhi,
and
E.Di Cera
(2009).
Stabilization of the E* form turns thrombin into an anticoagulant.
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J Biol Chem,
284,
20034-20040.
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PDB code:
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E.Di Cera
(2009).
Serine proteases.
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IUBMB Life,
61,
510-515.
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P.S.Gandhi,
M.J.Page,
Z.Chen,
L.Bush-Pelc,
and
E.Di Cera
(2009).
Mechanism of the anticoagulant activity of thrombin mutant W215A/E217A.
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J Biol Chem,
284,
24098-24105.
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PDB codes:
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P.Gros,
F.J.Milder,
and
B.J.Janssen
(2008).
Complement driven by conformational changes.
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Nat Rev Immunol,
8,
48-58.
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A.Lazic,
D.H.Goetz,
A.M.Nomura,
A.B.Marnett,
and
C.S.Craik
(2007).
Substrate modulation of enzyme activity in the herpesvirus protease family.
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J Mol Biol,
373,
913-923.
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PDB code:
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L.V.Kozlov,
O.O.Burdelev,
S.V.Bureeva,
and
A.P.Kaplun
(2007).
[Artificial inhibition of the complement system]
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Bioorg Khim,
33,
485-510.
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G.H.Caughey
(2006).
A Pulmonary Perspective on GASPIDs: Granule-Associated Serine Peptidases of Immune Defense.
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Curr Respir Med Rev,
2,
263-277.
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L.W.Yang,
and
I.Bahar
(2005).
Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes.
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Structure,
13,
893-904.
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K.Ponnuraj,
Y.Xu,
K.Macon,
D.Moore,
J.E.Volanakis,
and
S.V.Narayana
(2004).
Structural analysis of engineered Bb fragment of complement factor B: insights into the activation mechanism of the alternative pathway C3-convertase.
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Mol Cell,
14,
17-28.
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PDB codes:
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C.Hink-Schauer,
E.Estébanez-Perpiñá,
E.Wilharm,
P.Fuentes-Prior,
W.Klinkert,
W.Bode,
and
D.E.Jenne
(2002).
The 2.2-A crystal structure of human pro-granzyme K reveals a rigid zymogen with unusual features.
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J Biol Chem,
277,
50923-50933.
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PDB codes:
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A.Sahu,
and
J.D.Lambris
(2000).
Complement inhibitors: a resurgent concept in anti-inflammatory therapeutics.
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Immunopharmacology,
49,
133-148.
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H.Jing,
Y.Xu,
M.Carson,
D.Moore,
K.J.Macon,
J.E.Volanakis,
and
S.V.Narayana
(2000).
New structural motifs on the chymotrypsin fold and their potential roles in complement factor B.
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EMBO J,
19,
164-173.
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PDB code:
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H.Jing,
K.J.Macon,
D.Moore,
L.J.DeLucas,
J.E.Volanakis,
and
S.V.Narayana
(1999).
Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D.
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EMBO J,
18,
804-814.
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PDB code:
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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.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
