Structural Mechanism for Statin Inhibition of HMG-CoA Reductase
Eva S. Istvan,1
Johann Deisenhofer12*
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.
1 Department of Biochemistry,
2 Howard Hughes Medical Institute, University of
Texas Southwestern Medical Center at Dallas, TX 75390-9050, USA.
*
To whom correspondence should be addressed. E-mail:
Johann.Deisenhofer{at}UTSouthwestern.edu
