Structural Mechanism for Statin Inhibition of HMG-CoA Reductase

@article{Istvan2001StructuralMF,
  title={Structural Mechanism for Statin Inhibition of HMG-CoA Reductase},
  author={Eva S. Istvan and Johann Deisenhofer},
  journal={Science},
  year={2001},
  volume={292},
  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… 
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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.
...

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