2qki: Difference between revisions
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==Overview== | ==Overview== | ||
Undesired complement activation is a major cause of tissue injury in | 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. | ||
==Disease== | |||
Known diseases associated with this structure: C3 deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=120700 120700]], Macular degeneration, age-related, 9 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=120700 120700]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Gros, P.]] | [[Category: Gros, P.]] | ||
[[Category: Halff, E | [[Category: Halff, E F.]] | ||
[[Category: Janssen, B | [[Category: Janssen, B J.C.]] | ||
[[Category: Lambris, J | [[Category: Lambris, J D.]] | ||
[[Category: ACE]] | [[Category: ACE]] | ||
[[Category: BR]] | [[Category: BR]] | ||
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[[Category: immunity]] | [[Category: immunity]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:40:06 2008'' | ||
Revision as of 19:40, 21 February 2008
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Human C3c in complex with the inhibitor compstatin
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: C3 deficiency OMIM:[120700], Macular degeneration, age-related, 9 OMIM:[120700]
About this StructureAbout this Structure
2QKI is a Protein complex structure of sequences from Homo sapiens with , , , and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Structure of compstatin in complex with complement component C3c reveals a new mechanism of complement inhibition., Janssen BJ, Halff EF, Lambris JD, Gros P, J Biol Chem. 2007 Oct 5;282(40):29241-7. Epub 2007 Aug 6. PMID:17684013
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