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Crystal structure of the anthrax lethal factor


Lethal factor (LF) is a protein (relative molecular mass 90,000) that is critical in the pathogenesis of anthrax1,2,3. It is a highly specific protease that cleaves members of the mitogen-activated protein kinase kinase (MAPKK) family near to their amino termini, leading to the inhibition of one or more signalling pathways4,5,6. 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 cleavage. Domain II resembles the ADP-ribosylating toxin from Bacillus cereus, but the active site has been mutated and recruited to augment substrate recognition. 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 catalytic centre; it also resembles domain I. The structure thus reveals a protein that has evolved through a process of gene duplication, mutation and fusion, into an enzyme with high and unusual specificity.

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Figure 1: Stereo ribbon representation of LF, coloured by domain.
Figure 2: Sequence of LF, coloured as in Fig. 1, with secondary structure indicated.
Figure 3: Stereo representation of the active site centre of LF.
Figure 4: Molecular surface of LF coloured by charge (red, negative; blue, positive), with the model of the MAPKK-2 N-terminal peptide shown in ball-and-stick representation.


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We thank L. Bankston for discussion and D. Hsu for LF preparations. We thank and acknowledge the staff and facilities of the synchrotron sources at SSRL, Stanford; SRS, Daresbury; ESRF, Grenoble; APS, Chicago; and National Synchrotron Light Source, Brookhaven. Supported by grants from the Medical Research Council and the National Institutes of Health.

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Correspondence to Robert C. Liddington.

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Table 1. Data collection summary for Lethal Factor crystals.

Figure 1

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Pannifer, A., Wong, T., Schwarzenbacher, R. et al. Crystal structure of the anthrax lethal factor. Nature 414, 229–233 (2001).

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