ABSTRACT
The anaphylatoxin C5a is derived from the complement component C5 during activation of the complement cascade. It is an important component in the pathogenesis of a number of inflammatory diseases. NMR structures of human and porcine C5a have been reported; these revealed a four-helix bundle stabilized by three disulfide bonds. The crystal structure of human desArg-C5a has now been determined in two crystal forms. Surprisingly, the protein crystallizes as a dimer and each monomer in the dimer has a three-helix core instead of the four-helix bundle noted in the NMR structure determinations. Furthermore, the N-terminal helices of the two monomers occupy different positions relative to the three-helix core and are completely different from the NMR structures. The physiological significance of these structural differences is unknown.
Subject(s)
Complement C5a, des-Arginine/chemistry , Complement C5a, des-Arginine/metabolism , Crystallography, X-Ray , Humans , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Protein Binding , Protein Multimerization , Protein Structure, Quaternary , Protein Structure, Secondary , Protein Structure, Tertiary , Receptor, Anaphylatoxin C5a/chemistry , Receptor, Anaphylatoxin C5a/metabolismABSTRACT
Halopemide, which was identified by HTS to inhibit phospholipase D2 (PLD2), provided the basis for an exploratory effort to identify potent inhibitors of PLD2 for use as inflammatory mediators. Parallel synthesis and purification were utilized to rapidly identify orally available amide analogs derived from indole 2-carboxylic acids with superior potency versus PLD2.
