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Cyclosporin-protein complex controls genes.

Three research reports reveal new details of the molecular mechanism underlying cyclosporin's ability to prevent the rejection of transplanted organs and to slow fungal infections.

Cyclosporin works by first attaching to a protein called cyclophilin. This molecular duo then suppresses the responses of the immune system, most likely by interacting with an enzyme called calcineurin.

By pushing the limits of both nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography, two research groups have visualized this duo. Their separate reports appear in the Jan. 7 Nature.

Earlier computer models had shown multiple connections between the two kinds of molecules. But some of these connections, called hydrogen bonds, were different in the real complex, says Stephen W. Fesik of Abbott Laboratories in Abbott Park, Ill.

Fesik and his colleagues used sophisticated NMR techniques to determine the structure of cyclosporin-cyclophilin pairs in solution. "The structures [obtained by the two groups] are remarkably similar," he says.

Unlike many other proteins, which twist or bend to make a tight fit with their partner molecules, cyclophilin maintains its shape when it binds to cyclosporin, adds Malcolm D. Walkinshaw, a crystallographer with Sandoz Pharma Ltd. in Basel, Switzerland.

Walkinshaw and his colleagues made crystals of this duo. But determining the exact positions of the atoms proved quite difficult. As they crystallize, these molecules congeal to form layered rosettes containing 10 to 12 pairs, he says. Thus, he could not study lone pairs, as did Fesik's group. However, while probably not the biologically active form, the rosette provides key information about each pair's structure, he adds.

In the crystals obtained by the Sandoz team, each of five cyclophilin molecules attaches to one side of each of five cyclosporin molecules. The shape of cyclophilin seems to promote the formation of a five-molecule unit, Walkinshaw explains.

To avoid contact with water, the five cyclosporin molecules then proceed to seek out five other cyclosporin molecules and to snuggle up against them. Thus, 10 cyclophilins wind up facing outward, with 10 cyclosporins sandwiched between them.

Each cyclosporin molecule arranges its amino acids into a ring with various chemical side groups sticking out. The crystal structure reveals that one hydroxyl side group in cyclosporin actually forms a hydrogen bond with its aminoacid backbone and not with cyclophilin.

This link helps maintain the shape of the cyclosporin molecule as it attaches to cyclophilin, says Walkinshaw. Researchers can now consider these details when they use computers to design new, possibly more effective surrogates for cyclosporin.

Using genetic engineering techniques, Thomas G. Larson and Donald J. Nuss of the Roche Institute of Molecular Biology in Nutley, N.J., have confirmed that this complex exerts its effects by altering the rate of gene expression. Cyclosporin ceases to work in chestnut blight fungus mutants lacking cyclophilin (SN: 8/8/92, p.84), they report in the Jan. I Proceedings of the National Academy of Sciences.
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Author:Pennisi, Elizabeth
Publication:Science News
Date:Jan 9, 1993
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