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Science 23 June 1995:
Vol. 268. no. 5218, pp. 1758 - 1762
DOI: 10.1126/science.7792601
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Articles

Science, Vol 268, Issue 5218, 1758-1762
Copyright © 1995 by American Association for the Advancement of Science

articles

Crystal structure of Pseudomonas mevalonii HMG-CoA reductase at 3.0 angstrom resolution

CM Lawrence, VW Rodwell, and CV Stauffacher

Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.

The rate-limiting step in cholesterol biosynthesis in mammals is catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a four-electron oxidoreductase that converts HMG-CoA to mevalonate. The crystal structure of HMG-CoA reductase from Pseudomonas mevalonii was determined at 3.0 angstrom resolution by multiple isomorphous replacement. The structure reveals a tightly bound dimer that brings together at the subunit interface the conserved residues implicated in substrate binding and catalysis. These dimers are packed about a threefold crystallographic axis, forming a hexamer with 23 point group symmetry. Difference Fourier studies reveal the binding sites for the substrates HMG-CoA and reduced or oxidized nicotinamide adenine dinucleotide [NAD(H)] and demonstrate that the active sites are at the dimer interfaces. The HMG-CoA is bound by a domain with an unusual fold, consisting of a central alpha helix surrounded by a triangular set of walls of beta sheets and alpha helices. The NAD(H) is bound by a domain characterized by an antiparallel beta structure that defines a class of dinucleotide-binding domains.


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