The leucine-rich repeat (LRR) is a prevalent structural motif that mediates specific protein-protein interactions (Kobe and Deisenhofer 1995b). The LRR is defined by a region of 20–29 residues that contains the consensus sequence: XLXXLXLXXN, where L, N, and X are leucine, asparagine, and any residue, respectively. Typically, LRRs are displayed in 1–30 tandem copies within a protein.

The first crystalline structure of an LRR-containing protein revealed a new protein fold (Kobe and Deisenhofer 1993)(fig. 1A and B). In porcine ribonuclease inhibitor (RI [Hofsteenge 1997]), the LRRs are arranged tandemly in a horseshoe shape with 16-helices encasing a parallel-sheet of 17 strands. Hydrophobic forces between the consensus leucine residues appear to stabilize the-sheet. RI is able to bind tightly to members of the ribonuclease (RNase) A superfamily, which not only catalyze RNA degradation but also mediate angiogenesis, cytotoxicity, and the host-defense response (D’Alessio and Riordan 1997; Raines 1998; Leland and Raines 2001).