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The Crystal Structure of Recombinant proDer p 1, a Major House Dust Mite Proteolytic Allergen¹

Kåre Meno^2,*, Peter B. Thorsted^*, Henrik Ipsen^*, Ole Kristensen, Jørgen N. Larsen^*, Michael D. Spangfort^*, Michael Gajhede and Kaare Lund^*

^* ALK-Abelló A/S, Research Department, Hørsholm, Denmark; and Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Copenhagen, Denmark

Allergy to house dust mite is among the most prevalent allergic diseases worldwide. Most house dust mite allergic patients react to Der p 1 from Dermatophagoides pteronyssinus, which is a cysteine protease. To avoid heterogeneity in the sample used for crystallization, a modified recombinant molecule was produced. The sequence of the proDer p 1 allergen was modified to reduce glycosylation and to abolish enzymatic activity. The resulting rproDer p 1 preparation was homogenous and stable and yielded crystals diffracting to a resolution of 1.61 Å. The active site is located in a large cleft on the surface of the molecule. The 80-aa pro-peptide adopts a unique fold that interacts with the active site cleft and a substantial adjacent area on the mature region, excluding access to the cleft and the active site. Studies performed using crossed-line immunoelectrophoresis and IgE inhibition experiments indicated that several epitopes are covered by the pro-peptide and that the epitopes on the recombinant mature molecule are indistinguishable from those on the natural one. The structure confirms previous results suggesting a preference for aliphatic residues in the important P2 position in substrates. Sequence variations in related species are concentrated on the surface, which explains the existence of cross-reacting and species-specific antibodies. This study describes the first crystal structure of one of the clinically most important house dust mite allergens, the cysteine protease Der p 1.

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