1DQ9

COMPLEX OF CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH HMG-COA

Summary for 1DQ9

• Entry DOI: 10.2210/pdb1dq9/pdb
• Descriptor: PROTEIN (HMG-COA REDUCTASE), 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A (2 entities in total)
• Functional Keywords: oxidoreductase, cholesterol biosynthesis, hmg-coa, nadph
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Multi-pass membrane protein: P04035
• Total number of polymer chains: 4
• Total formula weight: 203712.57

Authors

Istvan, E.S.,Palnitkar, M.,Buchanan, S.K.,Deisenhofer, J. (deposition date: 1999-12-30, release date: 2000-03-08, Last modification date: 2024-02-07)

Primary citation

Istvan, E.S.,Palnitkar, M.,Buchanan, S.K.,Deisenhofer, J.
Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis.
EMBO J., 19:819-830, 2000

PubMed 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.

PubMed: 10698924
DOI: 10.1093/emboj/19.5.819

Experimental method

X-RAY DIFFRACTION (2.8 Å)