Structural Mechanism for Statin Inhibition of HMG-CoA Reductase
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...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2001-05, Vol.292 (5519), p.1160-1164 |
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| creator | Istvan, Eva S. Deisenhofer, Johann |
| description | 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. |
| doi_str_mv | 10.1126/science.1059344 |
| format | Article |
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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. 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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.</description><subject>Active sites</subject><subject>Acyl Coenzyme A - antagonists & inhibitors</subject><subject>Acyl Coenzyme A - metabolism</subject><subject>ADVANCED LIGHT SOURCE</subject><subject>ADVANCED LIGHT SOURCE ALS</subject><subject>Analysis</subject><subject>Anticholesteremic agents</subject><subject>Anticholesteremic Agents - chemistry</subject><subject>Anticholesteremic Agents - metabolism</subject><subject>Anticholesteremic Agents - pharmacology</subject><subject>Atoms</subject><subject>Binding Sites</subject><subject>Biochemistry</subject><subject>Biological and medical sciences</subject><subject>Catalysts</subject><subject>Catalytic Domain</subject><subject>Cholesterol</subject><subject>Crystalline structure</subject><subject>Crystallography, X-Ray</subject><subject>Crystals</subject><subject>Developed Nations</subject><subject>Drug Therapy</subject><subject>Enzymes</subject><subject>Fish culture</subject><subject>Fundamental and applied biological sciences. 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(US)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural Mechanism for Statin Inhibition of HMG-CoA Reductase</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2001-05-11</date><risdate>2001</risdate><volume>292</volume><issue>5519</issue><spage>1160</spage><epage>1164</epage><pages>1160-1164</pages><issn>0036-8075</issn><issn>0193-4511</issn><eissn>1095-9203</eissn><coden>SCIEAS</coden><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.</abstract><cop>Washington, DC</cop><pub>American Society for the Advancement of Science</pub><pmid>11349148</pmid><doi>10.1126/science.1059344</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2001-05, Vol.292 (5519), p.1160-1164 |
| issn | 0036-8075 0193-4511 1095-9203 |
| language | eng |
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| source | MEDLINE; Science Magazine; JSTOR Archive Collection A-Z Listing |
| subjects | Active sites Acyl Coenzyme A - antagonists & inhibitors Acyl Coenzyme A - metabolism ADVANCED LIGHT SOURCE ADVANCED LIGHT SOURCE ALS Analysis Anticholesteremic agents Anticholesteremic Agents - chemistry Anticholesteremic Agents - metabolism Anticholesteremic Agents - pharmacology Atoms Binding Sites Biochemistry Biological and medical sciences Catalysts Catalytic Domain Cholesterol Crystalline structure Crystallography, X-Ray Crystals Developed Nations Drug Therapy Enzymes Fish culture Fundamental and applied biological sciences. Psychology Humans Hydrogen Bonding Hydroxymethylglutaryl CoA Reductases - chemistry Hydroxymethylglutaryl CoA Reductases - metabolism Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology INHIBITION Mathematical constants Models, Molecular Molecular biophysics Molecules Monomers OXIDOREDUCTASES Oxygen PARTICLE ACCELERATORS Pliability Protein Binding Protein Structure, Secondary Selector genes Structure in molecular biology |
| title | Structural Mechanism for Statin Inhibition of HMG-CoA Reductase |
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