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TitleStructural basis for therapeutic inhibition of complement C5.
Journal, issue, pagesNat Struct Mol Biol, Vol. 23, Issue 5, Page 378-386, Year 2016
Publish dateMar 28, 2016
AuthorsMatthijs M Jore / Steven Johnson / Devon Sheppard / Natalie M Barber / Yang I Li / Miles A Nunn / Hans Elmlund / Susan M Lea /
PubMed AbstractActivation 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 ...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.
External linksNat Struct Mol Biol / PubMed:27018802 / PubMed Central
MethodsEM (single particle) / X-ray diffraction / NMR (solution)
Resolution2.59 - 16.0 Å
Structure data

EMDB-8092:
Structure of the quaternary complex of complement C5 with two tick inhibitors (OmCI and RaCI) and a Fab derived from the therapeutic Eculizumab
Method: EM (single particle) / Resolution: 16.0 Å

PDB-5hcc:
Ternary complex of human Complement C5 with Ornithodoros moubata OmCI and Dermacentor andersoni RaCI3.
Method: X-RAY DIFFRACTION / Resolution: 2.59 Å

PDB-5hcd:
Ternary complex of human Complement C5 with Ornithodoros moubata OmCI and Rhipicephalus microplus RaCI2
Method: X-RAY DIFFRACTION / Resolution: 2.98 Å

PDB-5hce:
Ternary complex of human Complement C5 with Ornithodoros moubata OmCI and Rhipicephalus appendiculatus RaCI1
Method: X-RAY DIFFRACTION / Resolution: 3.12 Å

PDB-5iec:
Structural basis for therapeutic inhibition of complement C5
Method: SOLUTION NMR

Chemicals

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-CYS:
CYSTEINE

ChemComp-DIO:
1,4-DIETHYLENE DIOXIDE

ChemComp-HOH:
WATER

Source
  • Human (human)
  • rhipicephalus appendiculatus (arthropod)
  • Synthetic construct (others)
  • ornithodoros moubata (arthropod)
  • dermacentor andersoni (arthropod)
  • homo sapiens (human)
  • rhipicephalus microplus (southern cattle tick)
KeywordsIMMUNE SYSTEM / Complement / Inflammation / Inhibitor / Tick / BLOOD CLOTTING / complement inhibitor / RaCI / STRUCTURE FROM CYANA 3.96

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