A model for the C5a receptor and for its interaction with the ligand [corrected]

Abstract

A model of the C5a receptor was built based on the assumption that the seven membrane-spanning helices of known inward/outward direction are in an arrangement roughly similar to that in bacteriorhodopsin. Guidelines for the positioning of the helices were cysteine pairing, 'ridges into grooves' interdigitation of side chains and aromatic cluster formation. The chain segments protruding from the membrane are too short for folding into an independent ectodomain. The only longer segment (179-202) is tied down in its centre onto the membrane by a disulphide bridge and, thereby, made into two short loops as well. Ideas of the interaction of the C5a receptor with its ligand were derived mainly from the search for accommodation of the functionally essential arginine residues 40 and 74 of C5a. Asp82 is the only charged residue in a pocket approximately 20 A below the receptor surface and is conserved in the rhodopsin superfamily. It commends itself for binding Arg74 which is the tip of the flexible C-terminal chain of C5a, and rules out Arg40 in the structurally well-defined part of the molecule. The latter may bind to Glu180 at the bottom of a more shallow pocket which happens to resemble the substrate-binding site of trypsin.