Figure 53

The three-dimensional structure of DNase I. p-Strands (capital letters) are represented by arrows and a-helices by cylinders. Two six-stranded p-pleated sheets consisting of strands E, F, C, A, P, N (sheet 1) and strands G, H, J, K, M, L (sheet 2) are packed against each other forming the core of the enzyme. The flexible loop region connects p-strands H and G. The carbohydrate side chain is attached to N18 at the beginning of helix I. The disulfide bridge between Cl73 and C209 is indicated. (From Suck, D., Oefner, C., and Kabsch, W., EMBO J, 3, 2423-2430, 1984. With permission.)

between the human and bovine enzyme are located in the hydrophilic regions on the surface of the molecule. Consequently, the gathering of almost all the differences between human and bovine DNase I on the surface may explain the development of antiDNase I bodies in half of the patients who received multiple doses of bovine DNase I [12,29].

In recent years, hyperactive variants of human DNase I have been created by introducing basic amino acids at selected positions on the DNA-binding interface to generate attractive interactions with the negatively charged phosphates on the DNA backbone. These variants digest DNA more efficiently under physiological saline conditions and show a > 10,000-fold higher activity than wild-type rhDNase I [30].

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