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PDBsum entry 1hw8
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Oxidoreductase
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PDB id
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1hw8
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural mechanism for statin inhibition of hmg-Coa reductase.
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Authors
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E.S.Istvan,
J.Deisenhofer.
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Ref.
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Science, 2001,
292,
1160-1164.
[DOI no: ]
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PubMed id
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Abstract
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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 blocking access of this substrate to the
active site. Near the carboxyl terminus of HMGR, several catalytically relevant
residues are disordered in the enzyme-statin complexes. If these residues were
not flexible, they would sterically hinder statin binding.
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Figure 2.
Fig. 2. Statins exploit the conformational flexibility of HMGR
to create a hydrophobic binding pocket near the active site. (A)
Active site of human HMGR in complex with HMG, CoA, and NADP.
The active site is located at a monomer-monomer interface. One
monomer is colored yellow, the other monomer is in blue.
Selected side chains of residues that contact the substrates or
the statin are shown in a ball-and-stick representation (20).
Secondary structure elements are marked by black labels. HMG and
CoA are colored in magenta; NADP is colored in green. To
illustrate the molecular volume occupied by the substrates,
transparent spheres with a radius of 1.6 Å are laid over
the ball-and-stick representation of the substrates or the
statin. (B) Binding of rosuvastatin to HMGR. Rosuvastatin is
colored in purple; other colors and labels are as in (A). This
figure and Figs. 3 and 4 were prepared with Bobscript (22), GLR
(23), and POV-Ray (24).
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Figure 4.
Fig. 4. Mode of binding of compactin (A), simvastatin (B),
fluvastatin (C), cerivastatin (D), atorvastatin (E), and
rosuvastatin (F) to human HMGR. Interactions between the HMG
moieties of the statins and the protein are mostly ionic or
polar. They are similar for all inhibitors and are indicated by
the dotted lines. Numbers next to the lines indicate distances
in Å (13). The rigid hydrophobic groups of the statins are
situated in a shallow groove between helices L  1 and L
10.
Additional interactions between Arg590 and the fluorophenyl
group are present in the type 2 statins (C, D, E, F).
Atorvastatin and rosuvastatin form a hydrogen bond between
Ser565 and a carbonyl oxygen atom (atorvastatin) (E) or a
sulfone oxygen atom (rosuvastatin) (F).
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The above figures are
reprinted
by permission from the AAAs:
Science
(2001,
292,
1160-1164)
copyright 2001.
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