66
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Structural mechanism for statin inhibition of HMG-CoA reductase.

      Science (New York, N.Y.)

      Acyl Coenzyme A, antagonists & inhibitors, metabolism, Anticholesteremic Agents, chemistry, pharmacology, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Humans, Hydrogen Bonding, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Models, Molecular, Pliability, Protein Binding, Protein Structure, Secondary

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar range that effectively lower serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of the catalytic portion of human HMGR complexed with six different statins. The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. Near the carboxyl terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin binding.

          Related collections

          Author and article information

          Journal
          11349148
          10.1126/science.1059344

          Comments

          Comment on this article