Structure of Fab hGR-2 F6, a competitive antagonist of the glucagon receptor

The monoclonal antibody hGR-2 F6 has been raised against the human glucagon receptor and shown to act as a competitive antagonist. As a first step in the structural characterization of the receptor, the crystal structure of t he Fab fragment from this antibody is reported at 2.1 Angstrom resolution. The hGR-2 F6 Fab crystallizes in the orthorhombic space group P2(1)2(1)2, w ith unit-cell parameters a = 76.14, b = 133.74, c = 37.46 Angstrom. A model generated by homology modelling was used as an aid in the chain-tracing an d the Fab fragment structure was subsequently refined (final R factor = 21. 7%). The structure obtained exhibits the typical immunoglobulin fold. Compl ementarity-determining regions (CDRs) L1, L2, L3, H1 and H2 could be superp osed onto standard canonical CDR loops. The H3 loop could be classified acc ording to recently published rules regarding loop length, sequence and conf ormation. This loop is 14 residues long, with an approximate beta-hairpin g eometry, which is distorted somewhat by the presence of two trans proline r esidues at the beginning of the loop. It is expected that this H3 loop will facilitate the design of synthetic probes for the glucagon receptor that m ay be used to investigate receptor activity.