Statins are very effective drugs that are prescribed to lower blood cholesterol levels; their annual sales in the U.S. alone exceed $10 billion. The primary target of statins is the enzyme HMG-CoA reductase which catalyzes a chemical reaction producing mevalonate, a precursor molecule needed for our bodies' own cholesterol production. I will describe crystal structures, determined by X-ray crystallography, of the catalytic portion of human HMG-CoA reductase with and without bound reactants and inhibitors. The mechanism of inhibition of the enzyme by statins consists of a combination of steric hindrance by blocking the binding site of the major reactant, and of preventing the formation of the complete active site. A comparison of human and bacterial HMG-CoA reductases demonstrates difficulties of homology modeling of proteins that are distant in evolution.
ANL Physics Division Colloquium Schedule