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PDBsum entry 2i6s
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Hydrolase PDB id
2i6s

 

 

 

 

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Contents
Protein chain
497 a.a. *
Ligands
NAG-NAG-BMA-FUL
NAG-NAG-BMA
NAG-NAG
NAG ×2
Waters ×38
* Residue conservation analysis
PDB id:
2i6s
Name: Hydrolase
Title: Complement component c2a
Structure: Complement c2a fragment. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: c2a. Expressed in: mesocricetus auratus. Expression_system_taxid: 10036.
Resolution:
2.70Å     R-factor:   0.212     R-free:   0.287
Authors: F.J.Milder,H.C.A.Raaijmakers,D.A.A.Vandeputte,A.Schouten, E.G.Huizinga,R.A.Romijn,W.Hemrika,A.Roos,M.R.Daha,P.Gros
Key ref:
F.J.Milder et al. (2006). Structure of complement component C2A: implications for convertase formation and substrate binding. Structure, 14, 1587-1597. PubMed id: 17027507 DOI: 10.1016/j.str.2006.08.008
Date:
29-Aug-06     Release date:   17-Oct-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P06681  (CO2_HUMAN) -  Complement C2 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		752 a.a.
497 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.4.21.43  - classical-complement-pathway C3/C5 convertase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleaves component C3 at the carboxyl of Arg-77 of the alpha-chain to yield C3a and C3b, and component C5 at the carboxyl of Arg-74 of the alpha-chain to yield C5a and C5b.

 

 
DOI no: 10.1016/j.str.2006.08.008 Structure 14:1587-1597 (2006)
PubMed id: 17027507  
 
 
Structure of complement component C2A: implications for convertase formation and substrate binding.
F.J.Milder, H.C.Raaijmakers, M.D.Vandeputte, A.Schouten, E.G.Huizinga, R.A.Romijn, W.Hemrika, A.Roos, M.R.Daha, P.Gros.
 
  ABSTRACT  
 
C2a provides the catalytic center to the convertase complexes of the classical and lectin-binding pathways of complement activation. We determined two crystal structures of full-length C2a, with and without a pseudo ligand bound. Both structures reveal a near-active conformation of the catalytic center of the serine protease domains, while the von Willebrand factor A-type domains display an intermediate activation state of helix alpha7 with an open, activated metal-ion-dependent adhesion site. The open adhesion site likely serves to enhance the affinity for the ligand C4b, similar to "inside-out" signaling in integrins. Surprisingly, the N-terminal residues of C2a are buried in a crevice near helix alpha7, indicative of a structural switch between C2 and C2a. Extended loops on the protease domain possibly envelop the protruding anaphylatoxin domain of the substrate C3. Together with a putative substrate-induced completion of the oxyanion hole, this may contribute to the high substrate specificity of the convertases.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Crystal Structure of C2a
(A) Schematic representation of domain topology of C2 and formation of the C3 convertase.
(B) Electron density (2mF[o] − DF[c], φ[c]) of the glycan attached to Asn-447; Asn-447-GlcNac-GlcNac-Man are shown.
(C) Stereo ribbon representation of the C2a-Mn^2+ structure; the catalytic triad (blue) in the SP domain (orange), the linker region (light blue) between the SP and VWA domains (green; its N-terminal residue is indicated by a green sphere), the manganese ion (pink) bound at the MIDAS motif, and the six glycosylation sites (gray) are shown.
(D) Overlay of C2a (black) and Bb (1rrk, green) (Ponnuraj et al., 2004) superimposed on the SP domains; the different positions of the α7 helix in the VWA domains are indicated. 		Figure 3.
Figure 3. N-Terminal Residues of C2a
(A) Stereo figure showing the N-terminal residues (ball-and-stick) of C2a positioned in a crevice near the linker (blue) connecting the VWA (green) and SP (orange) domains. The C2a N terminus is anchored via Ile-225 and Ile-227, which are buried in underlying hydrophobic pockets.
(B) Overlay of C2a-Mn^2+ (green) and the closed α[L]-I domain (1xuo, yellow) in complex with a small-molecule antagonist (Wattanasin et al., 2005). The binding sites for the N-terminal segment in C2a and the antagonist partially overlap.
(C) Overlay of the N- and C-terminal regions of the VWA domain of C2a (green) and engineered Bb (1rrk, magenta) (Ponnuraj et al., 2004). In C2a, the N-terminal residues interact with α7, and Ile-225 and Ile-227 occupy hydrophobic pockets. In engineered Bb residues of the C-terminal end of α7 (Met-443 and Ile-444) occupy these hydrophobic pockets.
 
  The above figures are reprinted by permission from Cell Press: Structure (2006, 14, 1587-1597) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20467445 D.Serruto, R.Rappuoli, M.Scarselli, P.Gros, and J.A.van Strijp (2010).
Molecular mechanisms of complement evasion: learning from staphylococci and meningococci.
  Nat Rev Microbiol, 8, 393-399.  
19503103 S.H.Rooijakkers, J.Wu, M.Ruyken, R.van Domselaar, K.L.Planken, A.Tzekou, D.Ricklin, J.D.Lambris, B.J.Janssen, J.A.van Strijp, and P.Gros (2009).
Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor.
  Nat Immunol, 10, 721-727.
PDB code: 2win
19237749 V.Krishnan, Y.Xu, K.Macon, J.E.Volanakis, and S.V.Narayana (2009).
The structure of C2b, a fragment of complement component C2 produced during C3 convertase formation.
  Acta Crystallogr D Biol Crystallogr, 65, 266-274.
PDB code: 3erb
18064050 P.Gros, F.J.Milder, and B.J.Janssen (2008).
Complement driven by conformational changes.
  Nat Rev Immunol, 8, 48-58.  
17310251 F.J.Milder, L.Gomes, A.Schouten, B.J.Janssen, E.G.Huizinga, R.A.Romijn, W.Hemrika, A.Roos, M.R.Daha, and P.Gros (2007).
Factor B structure provides insights into activation of the central protease of the complement system.
  Nat Struct Mol Biol, 14, 224-228.
PDB code: 2ok5
17921140 G.T.Le, G.Abbenante, and D.P.Fairlie (2007).
Profiling the enzymatic properties and inhibition of human complement factor B.
  J Biol Chem, 282, 34809-34816.  
17098186 T.A.Springer (2006).
Complement and the multifaceted functions of VWA and integrin I domains.
  Structure, 14, 1611-1616.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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