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PDBsum entry 2i6q
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References listed in PDB file
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Key reference
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Title
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Structure of complement component c2a: implications for convertase formation and substrate binding.
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Authors
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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,
P.Gros.
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Ref.
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Structure, 2006,
14,
1587-1597.
[DOI no: ]
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PubMed id
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Abstract
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C2a provides the catalytic center to the convertase complexes of the classical
and lectin-binding pathways of complement activation. We determined two crystal
structures of full-length C2a, with and without a pseudo ligand bound. Both
structures reveal a near-active conformation of the catalytic center of the
serine protease domains, while the von Willebrand factor A-type domains display
an intermediate activation state of helix alpha7 with an open, activated
metal-ion-dependent adhesion site. The open adhesion site likely serves to
enhance the affinity for the ligand C4b, similar to "inside-out"
signaling in integrins. Surprisingly, the N-terminal residues of C2a are buried
in a crevice near helix alpha7, indicative of a structural switch between C2 and
C2a. Extended loops on the protease domain possibly envelop the protruding
anaphylatoxin domain of the substrate C3. Together with a putative
substrate-induced completion of the oxyanion hole, this may contribute to the
high substrate specificity of the convertases.
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Figure 1.
Figure 1. Crystal Structure of C2a
(A) Schematic
representation of domain topology of C2 and formation of the C3
convertase.
(B) Electron density (2mF[o] − DF[c], φ[c])
of the glycan attached to Asn-447; Asn-447-GlcNac-GlcNac-Man are
shown.
(C) Stereo ribbon representation of the C2a-Mn^2+
structure; the catalytic triad (blue) in the SP domain (orange),
the linker region (light blue) between the SP and VWA domains
(green; its N-terminal residue is indicated by a green sphere),
the manganese ion (pink) bound at the MIDAS motif, and the six
glycosylation sites (gray) are shown.
(D) Overlay of C2a
(black) and Bb (1rrk, green) (Ponnuraj et al., 2004)
superimposed on the SP domains; the different positions of the
α7 helix in the VWA domains are indicated.
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Figure 3.
Figure 3. N-Terminal Residues of C2a
(A) Stereo figure
showing the N-terminal residues (ball-and-stick) of C2a
positioned in a crevice near the linker (blue) connecting the
VWA (green) and SP (orange) domains. The C2a N terminus is
anchored via Ile-225 and Ile-227, which are buried in underlying
hydrophobic pockets.
(B) Overlay of C2a-Mn^2+ (green) and
the closed α[L]-I domain (1xuo, yellow) in complex with a
small-molecule antagonist (Wattanasin et al., 2005). The binding
sites for the N-terminal segment in C2a and the antagonist
partially overlap.
(C) Overlay of the N- and C-terminal
regions of the VWA domain of C2a (green) and engineered Bb
(1rrk, magenta) (Ponnuraj et al., 2004). In C2a, the N-terminal
residues interact with α7, and Ile-225 and Ile-227 occupy
hydrophobic pockets. In engineered Bb residues of the C-terminal
end of α7 (Met-443 and Ile-444) occupy these hydrophobic
pockets.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2006,
14,
1587-1597)
copyright 2006.
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