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631 a.a.
184 a.a.
292 a.a.
15 a.a.
_BR
__K
Key reference
DOI no: 10.1074/jbc.M704587200 J Biol Chem 282:29241-29247 (2007) PubMed id: 17684013
Structure of compstatin in complex with complement component C3c reveals a new mechanism of complement inhibition. B.J.Janssen, E.F.Halff, J.D.Lambris, P.Gros. ABSTRACT
Undesired complement activation is a major cause of tissue injury in various pathological conditions and contributes to several immune complex diseases. Compstatin, a 13-residue peptide, is an effective inhibitor of the activation of complement component C3 and thus blocks a central and crucial step in the complement cascade. The precise binding site on C3, the structure in the bound form, and the exact mode of action of compstatin are unknown. Here we present the crystal structure of compstatin in complex with C3c, a major proteolytic fragment of C3. The structure reveals that the compstatin-binding site is formed by the macroglobulin (MG) domains 4 and 5. This binding site is part of the structurally stable MG-ring formed by domains MG 1-6 and is far away from any other known binding site on C3. Compstatin does not alter the conformation of C3c, whereas compstatin itself undergoes a large conformational change upon binding. We propose a model in which compstatin sterically hinders the access of the substrate C3 to the convertase complexes, thus blocking complement activation and amplification. These insights are instrumental for further development of compstatin as a potential therapeutic.
Selected figure(s)
Figure 2.
FIGURE 2. Interactions between C3c and compstatin. C3c is colored gray, and compstatin is colored as in Fig. 1A. A, residues involved in van der Waals contact, observed in both complexes within the asymmetric unit of the crystal, are shown in stick representation. B, hydrogen bonds between C3c and compstatin and within compstatin itself, observed in both complexes within the asymmetric unit, are shown by yellow dotted lines. See supplemental Table II for all observed contacts between C3c and compstatin.Figure 4.
FIGURE 4. Model for inhibition by compstatin. A, two symmetry-related molecules of C3b contact each other at the compstatin-binding site in the crystal of C3b (19). Compstatin (wheat) is superposed onto a C3b molecule (surface representation) on the basis of the C3c-compstatin structure. The symmetry related C3b molecule (ribbon representation) clashes severely with compstatin. B, top diagram, schematic representation of the back-to-back binding of C3 to the convertase (based on crystal structures of C3 (18), C3b (19, 21), and factor Bb (33)). Bottom diagram, schematic representation of steric hindrance of C3 binding to the convertase induced by compstatin.The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 29241-29247) copyright 2007. Figures were selected by the author.
Literature references that cite this PDB file's key reference
PubMed id Reference
19960015 E.Wagner, and M.M.Frank (2010).
Therapeutic potential of complement modulation.Nat Rev Drug Discov, 9, 43-56.
19574954 B.J.Janssen, L.Gomes, R.I.Koning, D.I.Svergun, A.J.Koster, D.C.Fritzinger, C.W.Vogel, and P.Gros (2009).
Insights into complement convertase formation based on the structure of the factor B-cobra venom factor complex.EMBO J, 28, 2469-2478.
PDB codes: 3hrz 3hs0
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.
19006477 M.A.Ahmadi, and J.I.Lim (2008).
Pharmacotherapy of age-related macular degeneration.Expert Opin Pharmacother, 9, 3045-3052.
18844671 T.L.Chiu, C.Mulakala, J.D.Lambris, and Y.N.Kaznessis (2008).
Development of a new pharmacophore model that discriminates active compstatin analogs.Chem Biol Drug Des, 72, 249-256.
17989689 D.Ricklin, and J.D.Lambris (2007).
Complement-targeted therapeutics.Nat Biotechnol, 25, 1265-1275. 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 codes are shown on the right.
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