SOLUTION STRUCTURE OF A UNIQUE C5A SEMISYNTHETIC ANTAGONIST - IMPLICATIONS IN RECEPTOR-BINDING

The tertiary structure of a unique C5a receptor antagonist was determi ned by two-dimensional NMR spectroscopy. The core domain of this 8-kDa antagonist exists as an antiparallel helical bundle, similar to recom binant human (rh)-C5a. However, unlike C5a, the antagonist's C terminu s was found to be conformationally restricted along a groove between h elices one and four in the core domain. This conformational restrictio n situates C-terminal D-Arg 75 in a wedge between core residues Arg 46 and His 15. Correlation of the antagonist's tertiary structure with p oint mutation analysis revealed the formation of a positively charged contiguous contact surface comprised of D-Arg 75, Arg 46, Lys 49, and His 15. The significance of this surface in generating antagonist prop erties implies a single binding site with the C5a receptor and provide s a structural template for drug design.