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… 
Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
  • E. Istvan
  • Medicine, Chemistry
    American heart journal
  • 2002
TLDR
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, Medicine
    Atherosclerosis. Supplements
  • 2003
TLDR
Differences in statin structure and binding characteristics may partially contribute to differences in potency of HMG-CoA reductase inhibition and other pharmacologic properties.
Binding thermodynamics of statins to HMG-CoA reductase.
TLDR
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.
TLDR
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*
TLDR
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.
The increasingly complex mechanism of HMG-CoA reductase.
TLDR
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.
TLDR
The potential significance of alternative splicing as a mechanism contributing to variation in statin efficacy as well as the use of immortalized lymphocyte cell lines for identifying pharmacogenetically relevant polymorphisms and molecular mechanisms are discussed.
The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases
TLDR
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.
Synthesis and Biological Evaluation of Gem‐Difluoromethylenated Statin Derivatives as Highly Potent HMG‐CoA Reductase Inhibitors
HMG-CoA reductase inhibitors were widely used as lipid-lowing agents through effectively blocking the rate-limiting step of cholesterol biosynthesis. 8 analogs of Rosuvastatin were firstly prepared
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