The three-dimensional structure of human bactericidal permeability-increasing protein - Implications for understanding protein-lipopolysaccharide interactions

Gram-negative bacterial infections are often complicated by the inflammator y properties of lipopolysaccharides (LPS) on or released from the bacterial outer membrane. When present in the mammalian bloodstream, LPS can trigger a series of pathological changes, sometimes resulting in septic shock. Two related mammalian proteins, bactericidal/permeability-increasing protein ( BPI) and lipopolysaccharide-binding protein (LBP), are known to affect the LPS-induced inflammatory response and are, therefore, of clinical interest. The recently determined three-dimensional structure of human BPI provides information on the overall protein fold, domain organization, and conserved regions of these two proteins. In addition, the discovery of two apolar li pid binding pockets in BPI indicates a possible site of interaction with LP S. The BPI structure is a powerful tool for the design of site-directed mut ants, peptide mimetics/inhibitors, and BPI/LBP chimeras. These studies shou ld help further define the functions of BPI and LBP, and their mechanism of interaction with LPS. (C) 1998 Elsevier Science Inc.