Computational study of conformational changes in human 3-hydroxy-3-methylglutaryl coenzyme reductase induced by substrate binding

@article{Costa2018ComputationalSO,
  title={Computational study of conformational changes in human 3-hydroxy-3-methylglutaryl coenzyme reductase induced by substrate binding},
  author={Clauber Henrique Costa and Amanda Ruslana Santana Oliveira and Alberto Monteiro dos Santos and Kauȇ Santana da Costa and Anderson H. Lima and Cl{\'a}udio Nahum Alves and Jer{\^o}nimo Lameira},
  journal={Journal of Biomolecular Structure and Dynamics},
  year={2018},
  volume={37},
  pages={4374 - 4383}
}
Abstract The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is mainly involved in the regulation of cholesterol biosynthesis. HMGR catalyses the reduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate at the expense of two NADPH molecules in a two-step reversible reaction. In the present study, we constructed a model of human HMGR (hHMGR) to explore the conformational changes of HMGR in complex with HMG-CoA and NADPH. In addition, we analysed the complete… 
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References

SHOWING 1-10 OF 36 REFERENCES
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.
Crystal structure of the catalytic portion of human HMG‐CoA reductase: insights into regulation of activity and catalysis
TLDR
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.
The structure of the catalytic portion of human HMG-CoA reductase.
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.
TLDR
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.
Structural Features and Domain Movements Controlling Substrate Binding and Cofactor Specificity in Class II HMG-CoA Reductase.
TLDR
The structure of SpHMGR bound with its kinetically preferred NADPH cofactor suggests how NADPH-specific binding and recognition are achieved, and large, previously unknown conformational domain movements that may control HMGR substrate binding and enable cofactor exchange without intermediate release during the catalytic cycle are revealed.
Molecular modeling of the reaction pathway and hydride transfer reactions of HMG-CoA reductase.
TLDR
The results support the hypothesis that the pK(a) of an active site acidic group is modulated by the redox state of the cofactor and are in good agreement with the well-studied hydride transfer reactions catalyzed by liver alcohol dehydrogenase in calculated energy profile and reaction geometries despite different mechanistic functionalities.
Phosphorylation of Ser871 impairs the function of His865 of Syrian hamster 3-hydroxy-3-methylglutaryl-CoA reductase.
TLDR
It is concluded that the introduction of negative charge at position 871 impairs the function of His865, presumably by a specific electrostatic interaction, and a novel mechanism by which phosphorylation regulates activity is proposed.
Regulation of HMG-CoA reductase in mammals and yeast.
Human hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and statin sensitivity.
TLDR
To examine, if a statin-resistant, catalytically-active isoform of the human HMGCR could be generated, rationally altered the protein to include additional residues in the flap domain, which has a role in statin binding.
Regulation of HMG‐CoA reductase: identification of the site phosphorylated by the AMP‐activated protein kinase in vitro and in intact rat liver.
TLDR
Phosphopeptide mapping of native, 100 kd microsomal HMG‐CoA reductase confirms that this C‐terminal serine is the only major site phosphorylated in the intact enzyme by the AMP‐activated protein kinase.
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