CRYSTAL-STRUCTURE OF AN ENDOTOXIN-NEUTRALIZING PROTEIN FROM THE HORSESHOE-CRAB, LIMULUS ANTI-LPS FACTOR, AT 1.5 ANGSTROM RESOLUTION

Lipopolysaccharide (LPS), or endotoxin, is the major mediator of septi c shock, a serious complication of Gram-negative bacterial infections in humans. Molecules that bind LPS and neutralize its biological effec ts or enhance its clearance could have important clinical applications . Limulus anti-LPS factor (LALF) binds LPS tightly, and, in animal mod els, reduces mortality when administered before or after LPS challenge or bacterial infection. Here we present the high resolution structure of a recombinant LALF. It has a single domain consisting of three alp ha-helices packed against a four-stranded beta-sheet. The wedge-shaped molecule has a striking charge distribution and amphipathicity that s uggest how it can insert into membranes. The binding site for LPS prob ably involves an extended amphipathic loop, and we propose that two ma mmalian LPS-binding proteins will have a similar loop. The amphipathic loop structure may be used in the design of molecules with therapeuti c properties against septic shock.