Structural Features and Domain Movements Controlling Substrate Binding and Cofactor Specificity in Class II HMG-CoA Reductase
| Autor: | Bradley R. Miller, Yan Kung |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation Coenzyme A Coenzymes Reductase Crystallography X-Ray Biochemistry Article Cofactor Substrate Specificity Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Bacterial Proteins Protein Domains Oxidoreductase Binding site chemistry.chemical_classification Binding Sites 030102 biochemistry & molecular biology biology NAD Hydroxymethylglutaryl-CoA reductase Recombinant Proteins Kinetics Streptococcus pneumoniae 030104 developmental biology chemistry Hydroxymethylglutaryl-CoA-Reductases NADP-dependent biology.protein Acyl Coenzyme A NAD+ kinase Mevalonate pathway Oxidation-Reduction NADP Protein Binding |
| Zdroj: | Biochemistry. 57:654-662 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/acs.biochem.7b00999 |
| Popis: | The key mevalonate pathway enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) uses the cofactor NAD(P)H to reduce HMG-CoA to mevalonate in the production of countless metabolites and natural products. Although inhibition of HMGR by statin drugs is well-understood, several mechanistic details of HMGR catalysis remain unresolved, and the structural basis for the wide range of cofactor specificity for either NADH or NADPH among HMGRs from different organisms is also unknown. Here, we present crystal structures of HMGR from Streptococcus pneumoniae (SpHMGR) alongside kinetic data of the enzyme's cofactor preferences. Our structure of SpHMGR bound with its kinetically preferred NADPH cofactor suggests how NADPH-specific binding and recognition are achieved. In addition, our structure of HMG-CoA-bound SpHMGR reveals large, previously unknown conformational domain movements that may control HMGR substrate binding and enable cofactor exchange without intermediate release during the catalytic cycle. Taken together, this work provides critical new insights into both the HMGR reaction mechanism and the structural basis of cofactor specificity. |
| Databáze: | OpenAIRE |
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