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PMID: 10698924 Published · ppublish English Journal Article

Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis.

The EMBO journal ·Vol. 19 ·No. 5 ·2000-03-01 ·Pages 819-30

Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J

Abstract

3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the formation of mevalonate, the committed step in the biosynthesis of sterols and isoprenoids. The activity of HMGR is controlled through synthesis, degradation and phosphorylation to maintain the concentration of mevalonate-derived products. In addition to the physiological regulation of HMGR, the human enzyme has been targeted successfully by drugs in the clinical treatment of high serum cholesterol levels. Three crystal structures of the catalytic portion of human HMGR in complexes with HMG-CoA, with HMG and CoA, and with HMG, CoA and NADP(+), provide a detailed view of the enzyme active site. Catalytic portions of human HMGR form tight tetramers. The crystal structure explains the influence of the enzyme's oligomeric state on the activity and suggests a mechanism for cholesterol sensing. The active site architecture of human HMGR is different from that of bacterial HMGR; this may explain why binding of HMGR inhibitors to bacterial HMGRs has not been reported.

MeSH Terms
Amino Acid Sequence Binding Sites Catalysis Enzyme Activation Humans Hydroxymethylglutaryl CoA Reductases/chemistry,metabolism Molecular Sequence Data Protein Conformation Structure-Activity Relationship Substrate Specificity
Chemicals
Hydroxymethylglutaryl CoA Reductases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Istvan E S
Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, TX 75235-9050, USA.
Palnitkar M
Buchanan S K
Deisenhofer J
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.5.819
Published
2000-03-01
Pages
819-30
Language
English
Region
England
NLM ID
8208664
PMCID
PMC305622
Subset
IM
Databases
PDB
1DQ8, 1DQA, ADQ9
External Links
PubMed source DOI: 10.1093/emboj/19.5.819 PMC Full Text View journal details
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