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J. Biol. Chem., Vol. 278, Issue 22, 19933-19938, May 30, 2003

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Crystal Structure of a Statin Bound to a Class II Hydroxymethylglutaryl-CoA Reductase^*

Lydia Tabernero  , Victor W. Rodwell ¶ and Cynthia V. Stauffacher ||

From the School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom and the Departments of ^||Biological Sciences and ^¶Biochemistry, Purdue University, West Lafayette, Indiana 47907

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase is the primary target in the current clinical treatment of hypercholesterolemias with specific inhibitors of the "statin" family. Statins are excellent inhibitors of the class I (human) enzyme but relatively poor inhibitors of the class II enzymes of important bacterial pathogens. To investigate the molecular basis for this difference we determined the x-ray structure of the class II Pseudomonas mevalonii HMG-CoA reductase in complex with the statin drug lovastatin. The structure shows lovastatin bound in the active site and its interactions with residues critically involved in catalysis and substrate binding. Binding of lovastatin also displaces the flap domain of the enzyme, which contains the catalytic residue His-381. Comparison with the structures of statins bound to the human enzyme revealed a similar mode of binding but marked differences in specific interactions that account for the observed differences in affinity. We suggest that these differences might be exploited to develop selective class II inhibitors for use as antibacterial agents against pathogenic microorganisms.

Received for publication, December 20, 2002 , and in revised form, March 5, 2003.

^* This work was supported by National Institutes of Health Grant HL 52115 (to C. V. S.), by American Heart Association Grant 0150503N (to V. W. R.), and by a grant from the Lucille P. Markey Foundation to the Structural Biology Group at Purdue. Data collection facilities are supported in part by the Purdue Cancer Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence and requests for materials should be addressed. Tel.: 44-161-275-7794; Fax: 44-161-275-5082; E-mail: Lydia.Tabernero{at}man.ac.uk.

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This article has been cited by other articles:

				M. Hedl, L. Tabernero, C. V. Stauffacher, and V. W. Rodwell Class II 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductases J. Bacteriol., April 1, 2004; 186(7): 1927 - 1932. [Full Text] [PDF]