Statins’ structure blocks cholesterol

Cholesterol-clobbering drugs called statins do their good work via the molecular equivalent of a sit-down strike, report researchers in the May 11 Science. The researchers used X-ray crystallography to determine the detailed structure of six different types of statins. From these, they deduced that the proteins interrupt a cascade of cholesterol-building events by physically blocking the binding site of an enzyme called HMGR.

Millions of people in the United States have high concentrations of cholesterol in their blood, a situation that can lead to blocked arteries and heart disease. Statins inhibit the body’s cholesterol synthesis and, along with exercise and changes in diet, can dramatically reduce cholesterol counts. However, the molecular action of statins has remained largely unknown.

Now, Eva S. Istvan of the Howard Hughes Medical Institute at Washington University in Saint Louis and Johann Deisenhofer at the University of Texas Southwestern Medical Center in Dallas have uncovered some of this action.

Normally, HMGR’s role is to bring together two molecular components required for cholesterol synthesis. Statins stop this by sitting in the pocket on HMGR where the parts bind.

All statin molecules have an armlike part attached to a flat, winglike part, says Istvan. She and Deisenhofer argue that a statin molecule works because its arm sticks into the enzyme’s pocket and then its wing crumples down into the cavity, blocking any other molecules from binding there. The researchers also learned that part of HMGR’s binding pocket remains unoccupied by the current crop of statins, a discovery that might inspire drug designers to build better drugs.

Even new, improved statins wouldn’t get you off the hook if you eat a lot of fatty meat, however, says Istvan. “We weren’t designed to eat a high-fat diet,” which contains ready-made cholesterol, she says. Statins only block the biochemical mechanism for making cholesterol from scratch.