5WPK

Structure of the class II 3-hydroxy-3-methylglutaryl-CoA reductase from Streptococcus pneumoniae bound to HMG-CoA and in a partially closed conformation

Summary for 5WPK

• Entry DOI: 10.2210/pdb5wpk/pdb
• Descriptor: 3-hydroxy-3-methylglutaryl coenzyme A reductase, 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A, GLYCEROL, ... (5 entities in total)
• Functional Keywords: 3-hydroxy-3-methylglutaryl-coa reductase, hmg-coa, conformational change, oxidoreductase
• Biological source: Streptococcus pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 95714.03

Authors

Miller, B.R.,Kung, Y. (deposition date: 2017-08-04, release date: 2018-04-25, Last modification date: 2023-10-04)

Primary citation

Miller, B.R.,Kung, Y.
Structural Features and Domain Movements Controlling Substrate Binding and Cofactor Specificity in Class II HMG-CoA Reductase.
Biochemistry, 57:654-662, 2018

PubMed Abstract: 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.

PubMed: 29224355
DOI: 10.1021/acs.biochem.7b00999

Experimental method

X-RAY DIFFRACTION (2.3 Å)