2hr0
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Structure of Complement C3b: Insights into Complement Activation and Regulation
OverviewOverview
The human complement system is an important component of innate immunity., Complement-derived products mediate functions contributing to pathogen, killing and elimination. However, inappropriate activation of the system, contributes to the pathogenesis of immunological and inflammatory, diseases. Complement component 3 (C3) occupies a central position because, of the manifold biological activities of its activation fragments, including the major fragment, C3b, which anchors the assembly of, convertases effecting C3 and C5 activation. C3 is converted to C3b by, proteolysis of its anaphylatoxin domain, by either of two C3 convertases., This activates a stable thioester bond, leading to the covalent attachment, of C3b to cell-surface or protein-surface hydroxyl groups through, transesterification. The cleavage and activation of C3 exposes binding, sites for factors B, H and I, properdin, decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor 1 (CR1, CD35) and viral molecules such as vaccinia virus complement-control, protein. C3b associates with these molecules in different configurations, and forms complexes mediating the activation, amplification and regulation, of the complement response. Structures of C3 and C3c, a fragment derived, from the proteolysis of C3b, have revealed a domain configuration, including six macroglobulin domains (MG1-MG6; nomenclature follows ref. 5), arranged in a ring, termed the beta-ring. However, because neither C3 nor, C3c is active in complement activation and regulation, questions about, function can be answered only through direct observations on C3b. Here we, present a structure of C3b that reveals a marked loss of secondary, structure in the CUB (for 'complement C1r/C1s, Uegf, Bmp1') domain, which, together with the resulting translocation of the thioester domain provides, a molecular basis for conformational changes accompanying the conversion, of C3 to C3b. The total conformational changes make many proposed, ligand-binding sites more accessible and create a cavity that shields, target peptide bonds from access by factor I. A covalently bound, N-acetyl-l-threonine residue demonstrates the geometry of C3b attachment, to surface hydroxyl groups.
DiseaseDisease
Known diseases associated with this structure: C3 deficiency OMIM:[120700], Macular degeneration, age-related, 9 OMIM:[120700]
About this StructureAbout this Structure
2HR0 is a Protein complex structure of sequences from Homo sapiens with THC as ligand. Full crystallographic information is available from OCA.
ReferenceReference
The structure of complement C3b provides insights into complement activation and regulation., Abdul Ajees A, Gunasekaran K, Volanakis JE, Narayana SV, Kotwal GJ, Murthy HM, Nature. 2006 Nov 9;444(7116):221-5. Epub 2006 Oct 15. PMID:17051152
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