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TitleStructural insights into C3 convertase activity of the classical pathway of complement.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Page 993, Year 2025
Publish dateDec 18, 2025
AuthorsKarla I De la O Becerra / T Harma C Brondijk / Itziar Serna Martin / Piet Gros /
PubMed AbstractImmune protection by the complement system depends on C3 cleavage by C3 convertases that is critical to all three activation pathways. Structural data on convertase formation in the classical pathway ...Immune protection by the complement system depends on C3 cleavage by C3 convertases that is critical to all three activation pathways. Structural data on convertase formation in the classical pathway and on C3-substrate binding to convertases is lacking. We present the cryo-EM structures of the proconvertase (C4b2), convertase (C4b2b), and convertase-substrate complex (C4b2b-C3) of the classical pathway. The data show that C2 and C4b form proconvertases and convertases like factor B and C3b of the alternative pathway. Substrate C3 binds C4b of the convertase through two interfaces: one also found in the SCIN-inhibited C3bBb dimer, and another facilitated by conformational changes in C3. Bending of C3 and swinging of the C2 protease bring the C3-scissile loop into the active site. The second, charged, C4b-interaction site favors C3- substrate binding, but upon cleavage repels product C3b. Thus, a charge switch-over mechanism effects the catalytic turnover of the convertases producing opsonin C3b.
External linksNat Commun / PubMed:41413058 / PubMed Central
MethodsEM (single particle)
Resolution3.5 - 4.3 Å
Structure data

EMDB-53198, PDB-9qj4:
Structure of the Complement classical and lectin pathway proconvertase, C4b2
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-53199, PDB-9qj5:
Structure of the Complement classical and lectin pathway proconvertase, C4b2
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-53217, PDB-9qk2:
Structure of the Complement classical and lectin pathway C3 convertase in complex with substrate C3
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-53288, PDB-9qpy:
Structure of the Complement classical and lectin pathway C3 convertase
Method: EM (single particle) / Resolution: 4.3 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsIMMUNE SYSTEM / Proconvertase / Complement / classical pathway / C4b2 / C3 convertase / Complement classical pathway / convertase-substrate complex / C3 substrate / convertase complex / Enzyme

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