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PDBsum entry 2b39
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Immune system
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PDB id
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2b39
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Contents |
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* Residue conservation analysis
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DOI no:
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J Mol Biol
361:115-127
(2006)
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PubMed id:
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The structure of bovine complement component 3 reveals the basis for thioester function.
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F.Fredslund,
L.Jenner,
L.B.Husted,
J.Nyborg,
G.R.Andersen,
L.Sottrup-Jensen.
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ABSTRACT
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The third component of complement (C3) is a 190 kDa glycoprotein essential for
eliciting the complement response. The protein consists of two polypeptide
chains (alpha and beta) held together with a single disulfide bridge. The
beta-chain is composed of six MG domains, one of which is shared with the
alpha-chain. The disulfide bridge connecting the chains is positioned in the
shared MG domain. The alpha-chain consists of the anaphylatoxin domain, three MG
domains, a CUB domain, an alpha(6)/alpha(6)-barrel domain and the C-terminal
C345c domain. An internal thioester in the alpha-chain of C3 (present in C4 but
not in C5) is cleaved during complement activation. This mediates covalent
attachment of the activated C3b to immune complexes and invading microorganisms,
thereby opsonizing the target. We present the structure of bovine C3 determined
at 3 Angstroms resolution. The structure shows that the ester is buried deeply
between the thioester domain and the properdin binding domain, in agreement with
the human structure. This domain interface is broken upon activation, allowing
nucleophile access. The structure of bovine C3 clearly demonstrates that the
main chain around the thioester undergoes a helical transition upon activation.
This rearrangement is proposed to be the basis for the high level of reactivity
of the thioester group. A strictly conserved glutamate residue is suggested to
function catalytically in thioester proteins. Structure-based design of
inhibitors of C3 activation may target a conserved pocket between the
alpha-chain and the beta-chain of C3, which appears essential for conformational
changes in C3.
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Selected figure(s)
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Figure 1.
Figure 1. Overall structure of native C3. (a) Ribbon
representation of the molecule with the domains coloured
individually and labelled. The Asn938 glycan, the linker region,
and the thioester are labelled G, L and T, respectively. The
thioester domain is labelled TED. (b) View towards the concave
surface of C3 (c) Close-up on the “valley” formed by the
MG1–MG6 domains and the linker region at the concave face. The
domains are coloured in the same manner in the following Figures.
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Figure 5.
Figure 5. Hydrogen bonding and thioester integrity. (a) The
main chain hydrogen bond pattern around the thioester in bovine
C3. Except for the thioester, only main chain atoms are shown.
Hydrogen bonds from the carbonyl group of Met1014 to the amide
groups of either Met1017 or Thr1018 appear to be almost equally
favorable. (b) The same area in C3d. In this structure (RCSB
entry 1C3D), a Cys1010Ala mutant was used. (c) The hydrogen bond
patterns in native human C3 (RCSB entry 2A73) around the
thioester in the same orientation as in (a). (d) The hydrogen
bond pattern of human C4Adg (RCSB entry 1HZF) in the same area.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2006,
361,
115-127)
copyright 2006.
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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.S.Laursen,
K.R.Andersen,
I.Braren,
E.Spillner,
L.Sottrup-Jensen,
and
G.R.Andersen
(2011).
Substrate recognition by complement convertases revealed in the C5-cobra venom factor complex.
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EMBO J,
30,
606-616.
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PDB codes:
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D.J.Sukovich,
J.L.Seffernick,
J.E.Richman,
J.A.Gralnick,
and
L.P.Wackett
(2010).
Widespread head-to-head hydrocarbon biosynthesis in bacteria and role of OleA.
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Appl Environ Microbiol,
76,
3850-3862.
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D.J.Sukovich,
J.L.Seffernick,
J.E.Richman,
K.A.Hunt,
J.A.Gralnick,
and
L.P.Wackett
(2010).
Structure, function, and insights into the biosynthesis of a head-to-head hydrocarbon in Shewanella oneidensis strain MR-1.
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Appl Environ Microbiol,
76,
3842-3849.
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K.Li,
J.Gor,
and
S.J.Perkins
(2010).
Self-association and domain rearrangements between complement C3 and C3u provide insight into the activation mechanism of C3.
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Biochem J,
431,
63-72.
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R.H.Baxter,
S.Steinert,
Y.Chelliah,
G.Volohonsky,
E.A.Levashina,
and
J.Deisenhofer
(2010).
A heterodimeric complex of the LRR proteins LRIM1 and APL1C regulates complement-like immunity in Anopheles gambiae.
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Proc Natl Acad Sci U S A,
107,
16817-16822.
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PDB codes:
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W.J.Cook,
N.Galakatos,
W.C.Boyar,
R.L.Walter,
and
S.E.Ealick
(2010).
Structure of human desArg-C5a.
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Acta Crystallogr D Biol Crystallogr,
66,
190-197.
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PDB codes:
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V.Krishnan,
K.Ponnuraj,
Y.Xu,
K.Macon,
J.E.Volanakis,
and
S.V.Narayana
(2009).
The crystal structure of cobra venom factor, a cofactor for C3- and C5-convertase CVFBb.
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Structure,
17,
611-619.
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PDB code:
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F.Fredslund,
N.S.Laursen,
P.Roversi,
L.Jenner,
C.L.Oliveira,
J.S.Pedersen,
M.A.Nunn,
S.M.Lea,
R.Discipio,
L.Sottrup-Jensen,
and
G.R.Andersen
(2008).
Structure of and influence of a tick complement inhibitor on human complement component 5.
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Nat Immunol,
9,
753-760.
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PDB code:
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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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B.J.Janssen,
E.F.Halff,
J.D.Lambris,
and
P.Gros
(2007).
Structure of compstatin in complex with complement component C3c reveals a new mechanism of complement inhibition.
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J Biol Chem,
282,
29241-29247.
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PDB code:
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R.H.Baxter,
C.I.Chang,
Y.Chelliah,
S.Blandin,
E.A.Levashina,
and
J.Deisenhofer
(2007).
Structural basis for conserved complement factor-like function in the antimalarial protein TEP1.
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Proc Natl Acad Sci U S A,
104,
11615-11620.
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PDB code:
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C.Wiesmann,
K.J.Katschke,
J.Yin,
K.Y.Helmy,
M.Steffek,
W.J.Fairbrother,
S.A.McCallum,
L.Embuscado,
L.DeForge,
P.E.Hass,
and
M.van Lookeren Campagne
(2006).
Structure of C3b in complex with CRIg gives insights into regulation of complement activation.
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Nature,
444,
217-220.
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PDB codes:
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F.J.Milder,
H.C.Raaijmakers,
M.D.Vandeputte,
A.Schouten,
E.G.Huizinga,
R.A.Romijn,
W.Hemrika,
A.Roos,
M.R.Daha,
and
P.Gros
(2006).
Structure of complement component C2A: implications for convertase formation and substrate binding.
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Structure,
14,
1587-1597.
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PDB codes:
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N.Nishida,
T.Walz,
and
T.A.Springer
(2006).
Structural transitions of complement component C3 and its activation products.
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Proc Natl Acad Sci U S A,
103,
19737-19742.
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T.A.Springer
(2006).
Complement and the multifaceted functions of VWA and integrin I domains.
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Structure,
14,
1611-1616.
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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
