Crystal structure of an endotoxin-neutralizing protein from the horseshoe crab, Limulus anti-LPS factor, at 1.5 A resolution.
Lipopolysaccharide (LPS), or endotoxin, is the major mediator of septic shock, a serious complication of Gram-negative bacterial infections in humans. Molecules that bind LPS and neutralize its biological effects or enhance its clearance could have important clinical applications. Limulus anti-LPS factor (LALF) binds LPS tightly, and, in animal models, 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 alpha-helices packed against a four-stranded beta-sheet. The wedge-shaped molecule has a striking charge distribution and amphipathicity that suggest how it can insert into membranes. The binding site for LPS probably involves an extended amphipathic loop, and we propose that two mammalian LPS-binding proteins will have a similar loop. The amphipathic loop structure may be used in the design of molecules with therapeutic properties against septic shock.
Hoess
A
A
Laboratory of X-Ray Crystallography, Dana-Farber Cancer Institute, Boston, MA.
Watson
S
S
Siber
G R
GR
Liddington
R
R
D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry*; D023181:Antimicrobial Cationic Peptides; D060829:Arthropod Proteins; D001665:Binding Sites; D015195:Drug Design; D006737:Horseshoe Crabs; D006863:Hydrogen-Ion Concentration; D007447:Invertebrate Hormones / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods
D000925:Anticoagulants; D023181:Antimicrobial Cationic Peptides; D060829:Arthropod Proteins; D007447:Invertebrate Hormones; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; C034705:antilipopolysaccharide factor (Limulus)