The structure of human porphobilinogen deaminase at 2.8 Å: the molecular basis of acute intermittent porphyria
Résumé
Mutations in the human porphobilinogen deaminase gene cause the inherited defect, acute intermittent porphyria. Here we report the structure of the human ubiquitous porphobilinogen deaminase mutant, Arg167Gln, that has been determined by X-ray crystallography and refined to 2.8 Å resolution (Rfactor=0.26, Rfree=0.29). The protein crystallized in space group P21212 with two molecules in the asymmetric unit (a = 81.0 Å, b = 104.4 Å, c = 109.7 Å). Phases were obtained by molecular replacement using the E. coli porphobilinogen deaminase structure as a search model. The human enzyme is composed of three domains each of approximately 110 amino acids and possesses a dipyrromethane cofactor at the active site which is located between domains 1 and 2. An ordered sulphate ion is hydrogen bonded to Arg26 and Ser28 at the proposed substrate binding site in domain 1. An insert of 29 amino acid residues, present only in mammalian porphobilinogen deaminase enzymes, has been modelled into domain 3 where it extends helix α23 and forms a β-hairpin structure that contributes to a continuous hydrogen bonding network spanning domains 1 and 3. The structural and functional implications of the Arg167Gln mutation and other mutations that result in acute intermittent porphyria are discussed.
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