Structural Mechanism for Statin Inhibition of HMG-CoA Reductase

  title={Structural Mechanism for Statin Inhibition of HMG-CoA Reductase},
  author={Eva S. Istvan and Johann Deisenhofer},
  pages={1160 - 1164}
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… 

Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase.

  • E. Istvan
  • Chemistry, Biology
    American heart journal
  • 2002
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the committed step in cholesterol biosynthesis, which is the target of compounds that are very effective in lowering serum cholesterol levels.

Statin inhibition of HMG-CoA reductase: a 3-dimensional view.

  • E. Istvan
  • Chemistry, Biology
    Atherosclerosis. Supplements
  • 2003

Binding thermodynamics of statins to HMG-CoA reductase.

The thermodynamic dissection presented here provides a way to identify interactions that are critical for affinity and specificity in statins, and shows a clear correlation between binding affinity and binding enthalpy.

An Atomic-Level Perspective of HMG-CoA-Reductase: The Target Enzyme to Treat Hypercholesterolemia

This review provides an updated atomic-level perspective regarding the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR), linking the more recent data on this enzyme with a

Explaining statin inhibition effectiveness of HMG-CoA reductase by quantum biochemistry computations.

Clinical data as well as IC(50) values of these cholesterol-lowering drugs are successfully explained only after stabilization of the calculated total binding energy for a larger size of the ligand-interacting HGMR region, one with a radius of at least 12.0 Å.

Crystal Structure of a Statin Bound to a Class II Hydroxymethylglutaryl-CoA Reductase*

The x-ray structure of the class II Pseudomonas mevalonii HMG-CoA reductase in complex with the statin drug lovastatin shows a similar mode of binding but marked differences in specific interactions that account for the observed differences in affinity, which might be exploited to develop selective class II inhibitors for use as antibacterial agents against pathogenic microorganisms.

Fine-Tuning of Nitrogen-Containing Bisphosphonate Esters that Potently Induce Degradation of HMG-CoA Reductase

A systematic structure-activity relationship study is performed on HMG-CoA reductase to optimize its activity and physicochemical properties, specifically focusing on the reduction of lipophilicity, suggesting the mono-fluorination of saturated alkyl groups as a useful strategy to balance potency and lipophILicity of the lead compounds.

The increasingly complex mechanism of HMG-CoA reductase.

HMG-CoA reductase serves as a model for how the combination of increasingly sophisticated experimental and computational methods can elucidate very complex enzyme mechanisms.

The role of HMGCR alternative splicing in statin efficacy.

The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases

Three-dimensional structures of the catalytic domain of HMG-CoA reductases from humans and from the bacterium Pseudomonas mevalonii, in conjunction with site-directed mutagenesis studies, have revealed details of the mechanism of catalysis.



The structure of the catalytic portion of human HMG-CoA reductase.

Crystal structure of the catalytic portion of human HMG‐CoA reductase: insights into regulation of activity and catalysis

The crystal structure of the catalytic portion of human HMGR explains the influence of the enzyme's oligomeric state on the activity and suggests a mechanism for cholesterol sensing.

Crystal structure of Pseudomonas mevalonii HMG-CoA reductase at 3.0 angstrom resolution.

The crystal structure of HMG-CoA reductase from Pseudomonas mevalonii was determined at 3.0 angstrom resolution by multiple isomorphous replacement and reveals a tightly bound dimer that brings together at the subunit interface the conserved residues implicated in substrate binding and catalysis.

The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.

Simvastatin enhanced phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase, inhibited apoptosis and accelerated vascular structure formation in vitro in an Akt-dependent manner, and promoted angiogenesis in ischemic limbs of normocholesterolemic rabbits.

Biosynthesis and characterization of (S)-and (R)-3-hydroxy-3-methylglutaryl coenzyme A.

Substrate-induced closure of the flap domain in the ternary complex structures provides insights into the mechanism of catalysis by 3-hydroxy-3-methylglutaryl-CoA reductase.

The structures of the ternary complexes reported here reveal a substrate-induced closing of the flap domain that completes the active site and aligns the catalytic histidine proximal to the thioester of HMG-CoA.

Low-density lipoprotein-independent effects of statins.

Pleiotropic effects are currently being given consideration when instituting combination therapy for patients at high cardiovascular risk and the challenge for the future will be to design and carry out appropriate clinical trials to establish their relative importance in the prevention of coronary artery disease.

Stimulation of bone formation in vitro and in rodents by statins.

It is shown that the statins, drugs widely used for lowering serum cholesterol, also enhance new bone formation in vitro and in rodents, and may have therapeutic applications for the treatment of osteoporosis.

Model bias in macromolecular crystal structures

Reduction of model bias in macromolecular crystallography through various omit-map techniques has been investigated. The two cases studied were the p21 protein complexed with GDP at 2.25 A resolution

Control of a Genetic Regulatory Network by a Selector Gene

It is shown that SCALLOPED, the DNA binding component of the selector protein complex for the Drosophila wing field, binds to and directly regulates the cis-regulatory elements of many individual target genes within the genetic regulatory network controlling wing development.