|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
642 a.a.
|
|
|
|
|
|
|
|
|
|
|
903 a.a.
|
|
|
|
|
|
|
|
|
|
|
119 a.a.
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Immune system
|
|
|
Title:
|
|
Crig bound to c3b
|
|
Structure:
|
|
Complement c3 beta chain. Chain: a. Complement c3 alpha chain. Chain: b. V-set and immunoglobulin domain-containing protein 4. Chain: s. Synonym: protein z39ig. Engineered: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
|
|
Biol. unit:
|
|
Hexamer (from
)
|
|
Resolution:
|
|
|
4.10Å
|
R-factor:
|
0.256
|
R-free:
|
0.330
|
|
|
Authors:
|
|
C.Wiesmann
|
Key ref:
|
|
C.Wiesmann
et al.
(2006).
Structure of C3b in complex with CRIg gives insights into regulation of complement activation.
Nature,
444,
217-220.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
12-Sep-06
|
Release date:
|
07-Nov-06
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P01024
(CO3_HUMAN) -
Complement C3 from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
1663 a.a.
642 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
Nature
444:217-220
(2006)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Structure of C3b in complex with CRIg gives insights into regulation of complement activation.
|
|
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,
M.van Lookeren Campagne.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
The complement system is a key part of the innate immune system, and is required
for clearance of pathogens from the bloodstream. After exposure to pathogens,
the third component of the complement system, C3, is cleaved to C3b which, after
recruitment of factor B, initiates formation of the alternative pathway
convertases. CRIg, a complement receptor expressed on macrophages, binds to C3b
and iC3b mediating phagocytosis of the particles, but it is unknown how CRIg
selectively recognizes proteolytic C3-fragments and whether binding of CRIg to
C3b inhibits convertase activation. Here we present the crystal structure of C3b
in complex with CRIg and, using CRIg mutants, provide evidence that CRIg acts as
an inhibitor of the alternative pathway of complement. The structure shows that
activation of C3 induces major structural rearrangements, including a dramatic
movement (>80 A) of the thioester-bond-containing domain through which C3b
attaches to pathogen surfaces. We show that CRIg is not only a phagocytic
receptor, but also a potent inhibitor of the alternative pathway convertases.
The structure provides insights into the complex macromolecular structural
rearrangements that occur during complement activation and inhibition. Moreover,
our structure-function studies relating the structural basis of complement
activation and the means by which CRIg inhibits the convertases provide
important clues to the development of therapeutics that target complement.
|
|
|
|
|
|
| |
Selected figure(s)
|
|
|
|
| |
|
|
|
|
|
|
Figure 1.
Figure 1: Domain architecture and structure of C3 and the
C3b/C3c:CRIg complexes. a, Domain organization of C3; the
 -chain
is depicted in green, the  -chain
in cyan (ANA domain), orange, (CUB), blue (TED) and violet. The
red sphere indicates the thioester. b, Ribbon diagrams of native
C3; (left; ref. 8), C3b in complex with CRIg (centre) and C3c in
complex with CRIg (right). The surface of CRIg is shown in
yellow. Note the movement of the CUB and TED domain when
comparing C3 and C3b:CRIg. c, Schematic depiction of b from a
slightly different orientation; the hexagon and triangle
represent His 1104 and the residues that form the thioesterbond
in C3, respectively.
|
|
Figure 2.
Figure 2: CRIg binds to the beta- -chain
of C3b and C3c and inhibits the AP C3 and C5 convertases. a,
Complex between C3c (surface representation) and CRIg (ribbon
diagram). b, Surface representation of CRIg, rotated 180°
from a. All atoms that are close to C3c/C3b are coloured like
the residues they are contacting in a. c, CRIg (filled symbols)
but not control protein (open symbols) reduces formation of C3a
des Arg formed on cleavage of C3 to C3a and C3b. d, CRIg (filled
symbols) but not control protein (open symbols) inhibits
generation of C5b, 6 formed on cleavage of C5 to C5a nd C5b.
Data are representative of three independent experiments.
|
|
|
|
|
|
| |
The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2006,
444,
217-220)
copyright 2006.
|
|
| |
Figures were
selected
by an automated process.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
H.P.Morgan,
C.Q.Schmidt,
M.Guariento,
B.S.Blaum,
D.Gillespie,
A.P.Herbert,
D.Kavanagh,
H.D.Mertens,
D.I.Svergun,
C.M.Johansson,
D.Uhrín,
P.N.Barlow,
and
J.P.Hannan
(2011).
Structural basis for engagement by complement factor H of C3b on a self surface.
|
| |
Nat Struct Mol Biol,
18,
463-470.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
J.Chen,
J.C.Crispín,
J.Dalle Lucca,
and
G.C.Tsokos
(2011).
A novel inhibitor of the alternative pathway of complement attenuates intestinal ischemia/reperfusion-induced injury.
|
| |
J Surg Res,
167,
e131-e136.
|
|
|
|
|
|
|
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.
|
| |
EMBO J,
30,
606-616.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
D.Serruto,
R.Rappuoli,
M.Scarselli,
P.Gros,
and
J.A.van Strijp
(2010).
Molecular mechanisms of complement evasion: learning from staphylococci and meningococci.
|
| |
Nat Rev Microbiol,
8,
393-399.
|
|
|
|
|
|
|
E.Wagner,
and
M.M.Frank
(2010).
Therapeutic potential of complement modulation.
|
| |
Nat Rev Drug Discov,
9,
43-56.
|
|
|
|
|
|
|
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.
|
| |
Science,
330,
1816-1820.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
H.Chen,
D.Ricklin,
M.Hammel,
B.L.Garcia,
W.J.McWhorter,
G.Sfyroera,
Y.Q.Wu,
A.Tzekou,
S.Li,
B.V.Geisbrecht,
V.L.Woods,
and
J.D.Lambris
(2010).
Allosteric inhibition of complement function by a staphylococcal immune evasion protein.
|
| |
Proc Natl Acad Sci U S A,
107,
17621-17626.
|
|
|
|
|
|
|
J.Bestebroer,
P.C.Aerts,
S.H.Rooijakkers,
M.K.Pandey,
J.Köhl,
J.A.van Strijp,
and
C.J.de Haas
(2010).
Functional basis for complement evasion by staphylococcal superantigen-like 7.
|
| |
Cell Microbiol,
12,
1506-1516.
|
|
|
|
|
|
|
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.
|
| |
Biochem J,
431,
63-72.
|
|
|
|
|
|
|
N.S.Laursen,
N.Gordon,
S.Hermans,
N.Lorenz,
N.Jackson,
B.Wines,
E.Spillner,
J.B.Christensen,
M.Jensen,
F.Fredslund,
M.Bjerre,
L.Sottrup-Jensen,
J.D.Fraser,
and
G.R.Andersen
(2010).
Structural basis for inhibition of complement C5 by the SSL7 protein from Staphylococcus aureus.
|
| |
Proc Natl Acad Sci U S A,
107,
3681-3686.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
P.K.Mallik,
K.Nishikawa,
A.J.Millis,
and
H.Shi
(2010).
Commandeering a biological pathway using aptamer-derived molecular adaptors.
|
| |
Nucleic Acids Res,
38,
e93.
|
|
|
|
|
|
|
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.
|
| |
Proc Natl Acad Sci U S A,
107,
16817-16822.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
R.Martínez-Barricarte,
M.Heurich,
F.Valdes-Cañedo,
E.Vazquez-Martul,
E.Torreira,
T.Montes,
A.Tortajada,
S.Pinto,
M.Lopez-Trascasa,
B.P.Morgan,
O.Llorca,
C.L.Harris,
and
S.Rodríguez de Córdoba
(2010).
Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation.
|
| |
J Clin Invest,
120,
3702-3712.
|
|
|
|
|
|
|
B.Borrell
(2009).
Fraud rocks protein community.
|
| |
Nature,
462,
970.
|
|
|
|
|
|
|
B.J.Janssen,
L.Gomes,
R.I.Koning,
D.I.Svergun,
A.J.Koster,
D.C.Fritzinger,
C.W.Vogel,
and
P.Gros
(2009).
Insights into complement convertase formation based on the structure of the factor B-cobra venom factor complex.
|
| |
EMBO J,
28,
2469-2478.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
B.Li,
H.Xi,
L.Diehl,
W.P.Lee,
L.Sturgeon,
J.Chinn,
L.Deforge,
R.F.Kelley,
C.Wiesmann,
M.van Lookeren Campagne,
and
S.S.Sidhu
(2009).
Improving therapeutic efficacy of a complement receptor by structure-based affinity maturation.
|
| |
J Biol Chem,
284,
35605-35611.
|
|
|
|
|
|
|
E.Torreira,
A.Tortajada,
T.Montes,
S.R.de Córdoba,
and
O.Llorca
(2009).
3D structure of the C3bB complex provides insights into the activation and regulation of the complement alternative pathway convertase.
|
| |
Proc Natl Acad Sci U S A,
106,
882-887.
|
|
|
|
|
|
|
H.Qu,
D.Ricklin,
and
J.D.Lambris
(2009).
Recent developments in low molecular weight complement inhibitors.
|
| |
Mol Immunol,
47,
185-195.
|
|
|
|
|
|
|
J.Wu,
Y.Q.Wu,
D.Ricklin,
B.J.Janssen,
J.D.Lambris,
and
P.Gros
(2009).
Structure of complement fragment C3b-factor H and implications for host protection by complement regulators.
|
| |
Nat Immunol,
10,
728-733.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
K.J.Katschke,
S.Stawicki,
J.Yin,
M.Steffek,
H.Xi,
L.Sturgeon,
P.E.Hass,
K.M.Loyet,
L.Deforge,
Y.Wu,
M.van Lookeren Campagne,
and
C.Wiesmann
(2009).
Structural and Functional Analysis of a C3b-specific Antibody That Selectively Inhibits the Alternative Pathway of Complement.
|
| |
J Biol Chem,
284,
10473-10479.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
K.Murata,
and
W.M.Baldwin
(2009).
Mechanisms of complement activation, C4d deposition, and their contribution to the pathogenesis of antibody-mediated rejection.
|
| |
Transplant Rev (Orlando),
23,
139-150.
|
|
|
|
|
|
|
S.H.Rooijakkers,
J.Wu,
M.Ruyken,
R.van Domselaar,
K.L.Planken,
A.Tzekou,
D.Ricklin,
J.D.Lambris,
B.J.Janssen,
J.A.van Strijp,
and
P.Gros
(2009).
Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor.
|
| |
Nat Immunol,
10,
721-727.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
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.
|
| |
Structure,
17,
611-619.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
D.Hatherley,
S.C.Graham,
J.Turner,
K.Harlos,
D.I.Stuart,
and
A.N.Barclay
(2008).
Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with CD47.
|
| |
Mol Cell,
31,
266-277.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
D.M.Appledorn,
A.McBride,
S.Seregin,
J.M.Scott,
N.Schuldt,
A.Kiang,
S.Godbehere,
and
A.Amalfitano
(2008).
Complex interactions with several arms of the complement system dictate innate and humoral immunity to adenoviral vectors.
|
| |
Gene Ther,
15,
1606-1617.
|
|
|
|
|
|
|
D.Ricklin,
and
J.D.Lambris
(2008).
Compstatin: a complement inhibitor on its way to clinical application.
|
| |
Adv Exp Med Biol,
632,
273-292.
|
|
|
|
|
|
|
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.
|
| |
Nat Immunol,
9,
753-760.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
H.G.Hocking,
A.P.Herbert,
D.Kavanagh,
D.C.Soares,
V.P.Ferreira,
M.K.Pangburn,
D.Uhrín,
and
P.N.Barlow
(2008).
Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations.
|
| |
J Biol Chem,
283,
9475-9487.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
K.U.Wendt,
M.S.Weiss,
P.Cramer,
and
D.W.Heinz
(2008).
Structures and diseases.
|
| |
Nat Struct Mol Biol,
15,
117-120.
|
|
|
|
|
|
|
M.C.Schuster,
D.Ricklin,
K.Papp,
K.S.Molnar,
S.J.Coales,
Y.Hamuro,
G.Sfyroera,
H.Chen,
M.S.Winters,
and
J.D.Lambris
(2008).
Dynamic structural changes during complement C3 activation analyzed by hydrogen/deuterium exchange mass spectrometry.
|
| |
Mol Immunol,
45,
3142-3151.
|
|
|
|
|
|
|
M.K.Pangburn,
V.P.Ferreira,
and
C.Cortes
(2008).
Discrimination between host and pathogens by the complement system.
|
| |
Vaccine,
26,
I15-I21.
|
|
|
|
|
|
|
M.Tanaka,
T.Nagai,
Y.Tsuneyoshi,
N.Sunahara,
T.Matsuda,
T.Nakamura,
S.Tsuyama,
K.Hasui,
O.FitzGerald,
and
T.Matsuyama
(2008).
Expansion of a unique macrophage subset in rheumatoid arthritis synovial lining layer.
|
| |
Clin Exp Immunol,
154,
38-47.
|
|
|
|
|
|
|
P.Gros,
F.J.Milder,
and
B.J.Janssen
(2008).
Complement driven by conformational changes.
|
| |
Nat Rev Immunol,
8,
48-58.
|
|
|
|
|
|
|
A.DeWan,
M.B.Bracken,
and
J.Hoh
(2007).
Two genetic pathways for age-related macular degeneration.
|
| |
Curr Opin Genet Dev,
17,
228-233.
|
|
|
|
|
|
|
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.
|
| |
J Biol Chem,
282,
29241-29247.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
B.J.Janssen,
R.J.Read,
A.T.Brünger,
and
P.Gros
(2007).
Crystallography: crystallographic evidence for deviating C3b structure.
|
| |
Nature,
448,
E1.
|
|
|
|
|
|
|
C.Q.Nguyen,
H.Kim,
J.G.Cornelius,
and
A.B.Peck
(2007).
Development of Sjogren's syndrome in nonobese diabetic-derived autoimmune-prone C57BL/6.NOD-Aec1Aec2 mice is dependent on complement component-3.
|
| |
J Immunol,
179,
2318-2329.
|
|
|
|
|
|
|
D.Ricklin,
and
J.D.Lambris
(2007).
Complement-targeted therapeutics.
|
| |
Nat Biotechnol,
25,
1265-1275.
|
|
|
|
|
|
|
F.J.Milder,
L.Gomes,
A.Schouten,
B.J.Janssen,
E.G.Huizinga,
R.A.Romijn,
W.Hemrika,
A.Roos,
M.R.Daha,
and
P.Gros
(2007).
Factor B structure provides insights into activation of the central protease of the complement system.
|
| |
Nat Struct Mol Biol,
14,
224-228.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
K.J.Katschke,
K.Y.Helmy,
M.Steffek,
H.Xi,
J.Yin,
W.P.Lee,
P.Gribling,
K.H.Barck,
R.A.Carano,
R.E.Taylor,
L.Rangell,
L.Diehl,
P.E.Hass,
C.Wiesmann,
and
M.van Lookeren Campagne
(2007).
A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritis.
|
| |
J Exp Med,
204,
1319-1325.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
M.van Lookeren Campagne,
C.Wiesmann,
and
E.J.Brown
(2007).
Macrophage complement receptors and pathogen clearance.
|
| |
Cell Microbiol,
9,
2095-2102.
|
|
|
|
|
|
|
P.Roversi,
O.Lissina,
S.Johnson,
N.Ahmat,
G.C.Paesen,
K.Ploss,
W.Boland,
M.A.Nunn,
and
S.M.Lea
(2007).
The structure of OMCI, a novel lipocalin inhibitor of the complement system.
|
| |
J Mol Biol,
369,
784-793.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
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.
|
| |
Proc Natl Acad Sci U S A,
104,
11615-11620.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
R.P.Rother,
S.A.Rollins,
C.F.Mojcik,
R.A.Brodsky,
and
L.Bell
(2007).
Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria.
|
| |
Nat Biotechnol,
25,
1256-1264.
|
|
|
|
|
|
|
M.Carroll
(2006).
Immunology: exposure of an executioner.
|
| |
Nature,
444,
159-160.
|
|
|
|
|
|
|
N.Nishida,
T.Walz,
and
T.A.Springer
(2006).
Structural transitions of complement component C3 and its activation products.
|
| |
Proc Natl Acad Sci U S A,
103,
19737-19742.
|
|
|
|
|
|
|
,
(0).
|
| |
,
(),
0.
|
|
|
|
|
|
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
code is
shown on the right.
|
 |
|
Links
