Crystal structure of the anthrax lethal factor

Lethal factor (LF) is a protein (relative molecular mass 90,000) that is cr itical in the pathogenesis of anthrax(1-3). It is a highly specific proteas e that cleaves members of the mitogen-activated protein kinase kinase (MAPK K) family near to their amino termini, leading to the inhibition of one or more signalling pathways(4-6). Here we describe the crystal structure of LF and its complex with the N terminus of MAPKK-2. LF comprises four domains: domain I binds the membrane-translocating component of anthrax toxin, the protective antigen (PA); domains II, III and IV together create a long deep groove that holds the 16-residue N-terminal tail of MAPKK-2 before cleavag e. Domain II resembles the ADP-ribosylating toxin from Bacillus cereus, but the active site has been mutated and recruited to augment substrate recogn ition. Domain III is inserted into domain II, and seems to have arisen from a repeated duplication of a structural element of domain II. Domain IV is distantly related to the zinc metalloprotease family, and contains the cata lytic centre; it also resembles domain I. The structure thus reveals a prot ein that has evolved through a process of gene duplication, mutation and fu sion, into an enzyme with high and unusual specificity.