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Crystal structure of the human c5a in complex with MEDI7814 a neutralising antibodyCrystal structure of the human c5a in complex with MEDI7814 a neutralising antibody
Structural highlights
DiseaseCO5_HUMAN Defects in C5 are the cause of complement component 5 deficiency (C5D) [MIM:609536. A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. Note=An association study of C5 haplotypes and genotypes in individuals with chronic hepatitis C virus infection shows that individuals homozygous for the C5_1 haplotype have a significantly higher stage of liver fibrosis than individuals carrying at least 1 other allele (PubMed:15995705). FunctionCO5_HUMAN Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled. Derived from proteolytic degradation of complement C5, C5 anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. C5a also stimulates the locomotion of polymorphonuclear leukocytes (chemokinesis) and direct their migration toward sites of inflammation (chemotaxis). Publication Abstract from PubMedC5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a-C5aR1 receptor are well defined, whereas C5a-C5aR2 receptor interactions are poorly understood. Here, we describe the generation of a human antibody, MEDI7814, that neutralizes C5a and C5adesArg binding to the C5aR1 and C5aR2 receptors, without affecting complement-mediated bacterial cell killing. Unlike other anti-C5a mAbs described, this antibody has been shown to inhibit the effects of C5a by blocking C5a binding to both C5aR1 and C5aR2 receptors. The crystal structure of the antibody in complex with human C5a reveals a discontinuous epitope of 22 amino acids. This is the first time the epitope for an antibody that blocks C5aR1 and C5aR2 receptors has been described, and this work provides a basis for molecular studies aimed at further understanding the C5a-C5aR2 receptor interaction. MEDI7814 has therapeutic potential for the treatment of acute inflammatory conditions in which both C5a receptors may mediate inflammation, such as sepsis or renal ischemia-reperfusion injury. Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors.,Colley CS, Popovic B, Sridharan S, Debreczeni JE, Hargeaves D, Fung M, An LL, Edwards B, Arnold J, England E, Eghobamien L, Sivars U, Flavell L, Renshaw J, Wickson K, Warrener P, Zha J, Bonnell J, Woods R, Wilkinson T, Dobson C, Vaughan TJ MAbs. 2017 Sep 27:1-14. doi: 10.1080/19420862.2017.1384892. PMID:28952876[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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