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PDBsum entry 5ubm
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Immune system/inhibitor
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PDB id
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5ubm
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Contents |
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233 a.a.
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147 a.a.
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115 a.a.
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PDB id:
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Immune system/inhibitor
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Title:
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Crystal structure of human c1s in complex with inhibitor gigastasin
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Structure:
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Complement c1s subcomponent. Chain: a. Synonym: c1 esterase,complement component 1 subcomponent s. Complement c1s subcomponent. Chain: b. Synonym: c1 esterase,complement component 1 subcomponent s. Gigastasin. Chain: i. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood plasma. Haementeria ghilianii. Organism_taxid: 6409. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.
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Resolution:
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2.50Å
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R-factor:
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0.179
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R-free:
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0.222
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Authors:
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S.S.Pang,J.C.Whisstock
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Key ref:
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S.S.Pang
et al.
(2017).
The Structural Basis for Complement Inhibition by Gigastasin, a Protease Inhibitor from the Giant Amazon Leech.
J Immunol,
199,
3883-3891.
PubMed id:
DOI:
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Date:
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20-Dec-16
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Release date:
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08-Nov-17
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PROCHECK
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Headers
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References
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P09871
(C1S_HUMAN) -
Complement C1s subcomponent from Homo sapiens
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Seq:
Struc:
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688 a.a.
233 a.a.
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Enzyme class:
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Chains A, B:
E.C.3.4.21.42
- complement subcomponent C1s.
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Reaction:
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Cleaves component C4 to C4a and C4b (Arg-|-Ala bond), and component C2 to C2a and C2b (Lys(or Arg)-|-Lys bond).
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DOI no:
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J Immunol
199:3883-3891
(2017)
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PubMed id:
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The Structural Basis for Complement Inhibition by Gigastasin, a Protease Inhibitor from the Giant Amazon Leech.
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S.S.Pang,
L.C.Wijeyewickrema,
L.Hor,
S.Tan,
E.Lameignere,
E.M.Conway,
A.M.Blom,
F.C.Mohlin,
X.Liu,
R.J.Payne,
J.C.Whisstock,
R.N.Pike.
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ABSTRACT
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Complement is crucial to the immune response, but dysregulation of the system
causes inflammatory disease. Complement is activated by three pathways:
classical, lectin, and alternative. The classical and lectin pathways are
initiated by the C1r/C1s (classical) and MASP-1/MASP-2 (lectin) proteases. Given
the role of complement in disease, there is a requirement for inhibitors to
control the initiating proteases. In this article, we show that a novel
inhibitor, gigastasin, from the giant Amazon leech, potently inhibits C1s and
MASP-2, whereas it is also a good inhibitor of MASP-1. Gigastasin is a poor
inhibitor of C1r. The inhibitor blocks the active sites of C1s and MASP-2, as
well as the anion-binding exosites of the enzymes via sulfotyrosine residues.
Complement deposition assays revealed that gigastasin is an effective inhibitor
of complement activation in vivo, especially for activation via the lectin
pathway. These data suggest that the cumulative effects of inhibiting both
MASP-2 and MASP-1 have a greater effect on the lectin pathway than the more
potent inhibition of only C1s of the classical pathway.
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Links
