HMG-CoA Reductase

PDB file 1DQA

Structure of the catalytic portion of human HMG-CoA Reductase. Structure determined by E. S. Istvan, M. Palnitkar, S. K. Buchanan, & J. Deisenhofer in 1999.

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The catalytic domain of the enzyme, when cleaved off of the membrane domain, assembles into a tetramer, consisting of two dimers. The enzyme has been crystallized with CoA and hydroxymethylglutarate (HMG) at the active site, instead of the natural substrate HMG-CoA.

Initially make the protein disappear by selecting Hide.

Select hetero-ligand, display as sticks, with color CPK. 
There are four active site complexes in this tetrameric form of the catalytic domain.


Zoom in to view CoA, NADP⁺, & HMG (hydroxymethylglutarate) at the active site.
Identify the positions of functional groups of the two coenzymes relative to HMG.
In particular, note the position of the nicotinamide ring of NADP⁺ relative to the carboxyl of HMG-CoA that would be reduced by NADPH.

Select ser872 and change its display. This residue's hydroxyl group is phosphorylated by AMP-Dependent Protein Kinase, leading to enzyme inhibition. 
Question: Is this regulatory site at the active site?

Now make the whole protein reappear by selecting protein, display as cartoon and color chain.
Where are the active sites located?  
Would you expect a monomer of the enzyme to be catalytically active?

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