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PDBsum entry 5hcc
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Immune system
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PDB id
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5hcc
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Contents |
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647 a.a.
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982 a.a.
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148 a.a.
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47 a.a.
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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 basis for therapeutic inhibition of complement c5.
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Authors
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M.M.Jore,
S.Johnson,
D.Sheppard,
N.M.Barber,
Y.I.Li,
M.A.Nunn,
H.Elmlund,
S.M.Lea.
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Ref.
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Nat Struct Biol, 2016,
23,
378-386.
[DOI no: ]
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PubMed id
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Abstract
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Activation of complement C5 generates the potent anaphylatoxin C5a and leads to
pathogen lysis, inflammation and cell damage. The therapeutic potential of C5
inhibition has been demonstrated by eculizumab, one of the world's most
expensive drugs. However, the mechanism of C5 activation by C5 convertases
remains elusive, thus limiting development of therapeutics. Here we identify and
characterize a new protein family of tick-derived C5 inhibitors. Structures of
C5 in complex with the new inhibitors, the phase I and phase II inhibitor OmCI,
or an eculizumab Fab reveal three distinct binding sites on C5 that all prevent
activation of C5. The positions of the inhibitor-binding sites and the ability
of all three C5-inhibitor complexes to competitively inhibit the C5 convertase
conflict with earlier steric-inhibition models, thus suggesting that a priming
event is needed for activation.
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