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PDBsum entry 1rtk
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Hormone/growth factor
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PDB id
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1rtk
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References listed in PDB file
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Key reference
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Title
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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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Authors
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K.Ponnuraj,
Y.Xu,
K.Macon,
D.Moore,
J.E.Volanakis,
S.V.Narayana.
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Ref.
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Mol Cell, 2004,
14,
17-28.
[DOI no: ]
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PubMed id
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Abstract
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The C-terminal fragment, Bb, of factor B combines with C3b to form the pivotal
C3-convertase, C3bBb, of alternative complement pathway. Bb consists of a von
Willebrand factor type A (vWFA) domain that is structurally similar to the I
domains of integrins and a serine protease (SP) domain that is in inactive
conformation. The structure of the C3bBb complex would be important in
deciphering the activation mechanism of the SP domain. However, C3bBb is labile
and not amenable to X-ray diffraction studies. We engineered a disulfide bond in
the vWFA domain of Bb homologous to that shown to lock I domains in active
conformation. The crystal structures of Bb(C428-C435) and its inhibitor
complexes reveal that the adoption of the "active" conformation by the
vWFA domain is not sufficient to activate the C3-convertase catalytic apparatus
and also provide insights into the possible mode of C3-convertase activation.
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Figure 1.
Figure 1. Cartoon Representation of C3-Convertase
FormationC3b attached to an activating surface binds factor B,
which undergoes conformational changes suitable for the cleavage
by factor D, resulting in C3-convertase formation.
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Figure 5.
Figure 5. Structures of Bb^C428-C435 Inhibitor Complexes(A)
Superposition of the active sites of Bb^C428-C435 (gold) and
Bb^C428-C435-BCX583 (light green) crystal structures. The
inhibitor (BCX583) covalently linked to Ser^195 is held in
position by hydrogen bonding to Asp^715(226) through a water
molecule (lavender). The L2 loop (red) is seen only in the
inhibitor complex structure.(B) Comparison of the active sites
of Bb^C428-C435-DIP and Bb^C428-C435. The backbone of the
inhibitor-bound Bb^C428-C435 is shown in light green color,
while the inhibitor-free Bb^C428-C435 is shown in gold color.
Covalently bound DIP molecule points its phosphoryl oxygen into
the putative oxyanion hole (marked with black star) and forces
it to acquire a tight β turn from a zymogen-like 3[10] helix
(transparent red color) conformation.(C) Stereo close-up of the
superposition of the 670(191)-674(194) segment of Bb^C428-C435
(gold) and Bb^C428-C435-DIP complex (light green). The
orientational difference of carbonyl oxygen of the residue
671(192) is indicated in the boxed area.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2004,
14,
17-28)
copyright 2004.
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