Structural mechanism for statin inhibition of HMG-CoA reductase
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.
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Statins competitively inhibit HMGCR, a rate-limiting step in cholesterol biosynthesis, effectively reducing endogenous production of cholesterol.
“The primary mechanism of action for statin drugs is to competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting step in cholesterol biosynthesis [181], effectively reducing the endogenous production of cholesterol.”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [181]
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- Authors
- Istvan, E. S., & Deisenhofer, J.
- Affiliations
- Department of Biochemistry,
- Howard Hughes Medical Institute (US)
- Corresponding author
- Deisenhofer, Johann
- Venue
- Science
- Published
- 2001-05-11
- Volume
- 292
- Issue
- 5519
- Pages
- 1160-1164
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2107841008
- Cited by
- 1,644
- References
- 0
- Citations by year
- 2026: 71 · 2025: 86 · 2024: 96 · 2023: 106 · 2022: 105 · 2021: 111 · 2020: 79 · 2019: 86 · 2018: 65 · 2017: 68 · 2016: 71 · 2015: 71 · 2014: 101 · 2013: 65 · 2012: 60
- FWCI
- 9.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- statins, HMG-CoA reductase, enzyme-inhibitor binding, cholesterol biosynthesis, hypercholesterolemia, protein structure, active site, catalytic residues, protein flexibility
- MeSH terms
- Acyl Coenzyme A, Anticholesteremic Agents, Binding Sites, Humans, Hydrogen Bonding, Hydroxymethylglutaryl CoA Reductases, Models, Molecular, Protein Binding, Protein Structure, Secondary, Crystallography, X-Ray, Pliability, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Catalytic Domain
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