PDBsum entry 1dqa

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Oxidoreductase PDB id
Jmol PyMol
Protein chain
409 a.a. *
COA ×4
MAH ×4
NAP ×4
Waters ×471
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Complex of the catalytic portion of human hmg-coa reductase with hmg, coa, and NADP+
Structure: Protein (hmg-coa reductase). Chain: a, b, c, d. Fragment: catalytic portion. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
2.00Å     R-factor:   0.168     R-free:   0.197
Authors: E.S.Istvan,M.Palnitkar,S.K.Buchanan,J.Deisenhofer
Key ref:
E.S.Istvan et al. (2000). Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. EMBO J, 19, 819-830. PubMed id: 10698924 DOI: 10.1093/emboj/19.5.819
30-Dec-99     Release date:   08-Mar-00    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P04035  (HMDH_HUMAN) -  3-hydroxy-3-methylglutaryl-coenzyme A reductase
888 a.a.
409 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Hydroxymethylglutaryl-CoA reductase (NADPH).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Mevalonate Biosynthesis
      Reaction: (R)-mevalonate + CoA + 2 NADP+ = (S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADPH
Bound ligand (Het Group name = MAH)
matches with 90.00% similarity
+ CoA
2 × NADP(+)
Bound ligand (Het Group name = NAP)
corresponds exactly
Bound ligand (Het Group name = COA)
matches with 82.00% similarity
+ 2 × NADPH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     integral to membrane   2 terms 
  Biological process     oxidation-reduction process   3 terms 
  Biochemical function     coenzyme binding     4 terms  


DOI no: 10.1093/emboj/19.5.819 EMBO J 19:819-830 (2000)
PubMed id: 10698924  
Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis.
E.S.Istvan, M.Palnitkar, S.K.Buchanan, J.Deisenhofer.
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.
  Selected figure(s)  
Figure 2.
Figure 2 Topology diagram of the human HMGR monomer. Colors for the three domains are as in Figure 1C. Helices are shown as outlined rectangles and strands are shown as solid arrows. The central helix L 10 in the L-domain is indicated by the outlined circle. Residues that participate in substrate binding as well as the N- and C-termini are indicated.
Figure 4.
Figure 4 Molecular surface of the dimer–dimer interface. (A) Atoms between 0.1 and 6 Šof the dimer–dimer interface are indicated by a color gradient of yellow to orange. (B) Colored according to residue type with hydrophobic residues (A, V, F, P, M, I, L, Y, W and G) in green, polar residues (S, T, H, C, N and Q) in white, K and R in blue, and D and E in red. This figure was prepared with GRASP (Nicholls et al., 1991), gl_render and POV-Ray.
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2000, 19, 819-830) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  20944214 G.W.Han, C.Bakolitsa, M.D.Miller, A.Kumar, D.Carlton, R.J.Najmanovich, P.Abdubek, T.Astakhova, H.L.Axelrod, C.Chen, H.J.Chiu, T.Clayton, D.Das, M.C.Deller, L.Duan, D.Ernst, J.Feuerhelm, J.C.Grant, A.Grzechnik, L.Jaroszewski, K.K.Jin, H.A.Johnson, H.E.Klock, M.W.Knuth, P.Kozbial, S.S.Krishna, D.Marciano, D.McMullan, A.T.Morse, E.Nigoghossian, L.Okach, R.Reyes, C.L.Rife, N.Sefcovic, H.J.Tien, C.B.Trame, H.van den Bedem, D.Weekes, Q.Xu, K.O.Hodgson, J.Wooley, M.A.Elsliger, A.M.Deacon, A.Godzik, S.A.Lesley, and I.A.Wilson (2010).
Structures of the first representatives of Pfam family PF06938 (DUF1285) reveal a new fold with repeated structural motifs and possible involvement in signal transduction.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 66, 1218-1225.
PDB codes: 2ra9 2re3
20693694 H.Xu (2010).
Enhancing MAD F(A) data for substructure determination.
  Acta Crystallogr D Biol Crystallogr, 66, 945-949.  
19778626 S.Li, J.A.Friesen, K.C.Holford, and D.W.Borst (2010).
Methyl farnesoate synthesis in the lobster mandibular organ: the roles of HMG-CoA reductase and farnesoic acid O-methyltransferase.
  Comp Biochem Physiol A Mol Integr Physiol, 155, 49-55.  
19437136 X.Cao, Z.Zong, X.Ju, Y.Sun, C.Dai, Q.Liu, and J.Jiang (2010).
Molecular cloning, characterization and function analysis of the gene encoding HMG-CoA reductase from Euphorbia Pekinensis Rupr.
  Mol Biol Rep, 37, 1559-1567.  
19291315 C.E.Ha, J.S.Ha, A.G.Theriault, and N.V.Bhagavan (2009).
Effects of statins on the secretion of human serum albumin in cultured HepG2 cells.
  J Biomed Sci, 16, 32.  
18853273 G.Lukács, T.Papp, F.Somogyvári, A.Csernetics, I.Nyilasi, and C.Vágvölgyi (2009).
Cloning of the Rhizomucor miehei 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene and its heterologous expression in Mucor circinelloides.
  Antonie Van Leeuwenhoek, 95, 55-64.  
19458199 G.S.Leichner, R.Avner, D.Harats, and J.Roitelman (2009).
Dislocation of HMG-CoA reductase and Insig-1, two polytopic endoplasmic reticulum proteins, en route to proteasomal degradation.
  Mol Biol Cell, 20, 3330-3341.  
19787197 J.P.Perchellet, E.M.Perchellet, K.R.Crow, K.R.Buszek, N.Brown, S.Ellappan, G.Gao, D.Luo, M.Minatoya, and G.H.Lushington (2009).
Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins.
  Int J Mol Med, 24, 633-643.  
19245650 J.S.Oakhill, J.W.Scott, and B.E.Kemp (2009).
Structure and function of AMP-activated protein kinase.
  Acta Physiol (Oxf), 196, 3.  
20005478 M.W.Medina, and R.M.Krauss (2009).
The role of HMGCR alternative splicing in statin efficacy.
  Trends Cardiovasc Med, 19, 173-177.  
18667535 C.M.Federovitch, Y.Z.Jones, A.H.Tong, C.Boone, W.A.Prinz, and R.Y.Hampton (2008).
Genetic and structural analysis of Hmg2p-induced endoplasmic reticulum remodeling in Saccharomyces cerevisiae.
  Mol Biol Cell, 19, 4506-4520.  
18817622 G.P.Chen, L.Yao, X.Lu, L.Li, and S.J.Hu (2008).
Tissue-specific effects of atorvastatin on 3-hydroxy-3-methylglutarylcoenzyme A reductase expression and activity in spontaneously hypertensive rats.
  Acta Pharmacol Sin, 29, 1181-1186.  
18219117 H.Xu, and C.M.Weeks (2008).
Rapid and automated substructure solution by Shake-and-Bake.
  Acta Crystallogr D Biol Crystallogr, 64, 172-177.  
19041767 J.S.Burg, D.W.Powell, R.Chai, A.L.Hughes, A.J.Link, and P.J.Espenshade (2008).
Insig regulates HMG-CoA reductase by controlling enzyme phosphorylation in fission yeast.
  Cell Metab, 8, 522-531.  
18559695 M.W.Medina, F.Gao, W.Ruan, J.I.Rotter, and R.M.Krauss (2008).
Alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase is associated with plasma low-density lipoprotein cholesterol response to simvastatin.
  Circulation, 118, 355-362.  
18802019 R.Burkhardt, E.E.Kenny, J.K.Lowe, A.Birkeland, R.Josowitz, M.Noel, J.Salit, J.B.Maller, I.Pe'er, M.J.Daly, D.Altshuler, M.Stoffel, J.M.Friedman, and J.L.Breslow (2008).
Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.
  Arterioscler Thromb Vasc Biol, 28, 2078-2084.  
17255938 J.W.Scott, F.A.Ross, J.K.Liu, and D.G.Hardie (2007).
Regulation of AMP-activated protein kinase by a pseudosubstrate sequence on the gamma subunit.
  EMBO J, 26, 806-815.  
17276918 L.D'Amico, I.C.Scott, B.Jungblut, and D.Y.Stainier (2007).
A mutation in zebrafish hmgcr1b reveals a role for isoprenoids in vertebrate heart-tube formation.
  Curr Biol, 17, 252-259.  
17666007 P.J.Espenshade, and A.L.Hughes (2007).
Regulation of sterol synthesis in eukaryotes.
  Annu Rev Genet, 41, 401-427.  
17701023 P.Weyrich, F.Machicao, H.Staiger, P.Simon, C.Thamer, J.Machann, F.Schick, A.Guirguis, A.Fritsche, N.Stefan, and H.U.Häring (2007).
Role of AMP-activated protein kinase gamma 3 genetic variability in glucose and lipid metabolism in non-diabetic whites.
  Diabetologia, 50, 2097-2106.  
16933277 A.H.Taban, J.Fu, J.Blake, A.Awano, C.Tittiger, and G.J.Blomquist (2006).
Site of pheromone biosynthesis and isolation of HMG-CoA reductase cDNA in the cotton boll weevil, Anthonomus grandis.
  Arch Insect Biochem Physiol, 62, 153-163.  
16817021 G.Shen, Y.Pang, W.Wu, Z.Liao, L.Zhao, X.Sun, and K.Tang (2006).
Cloning and characterization of a root-specific expressing gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase from Ginkgo biloba.
  Mol Biol Rep, 33, 117-127.  
16413480 J.L.Goldstein, R.A.DeBose-Boyd, and M.S.Brown (2006).
Protein sensors for membrane sterols.
  Cell, 124, 35-46.  
15983421 H.Xu, C.M.Weeks, and H.A.Hauptman (2005).
Optimizing statistical Shake-and-Bake for Se-atom substructure determination.
  Acta Crystallogr D Biol Crystallogr, 61, 976-981.  
15802646 S.S.Doun, J.W.Burgner, S.D.Briggs, and V.W.Rodwell (2005).
Enterococcus faecalis phosphomevalonate kinase.
  Protein Sci, 14, 1134-1139.  
15535874 J.A.Friesen, and V.W.Rodwell (2004).
The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases.
  Genome Biol, 5, 248.  
14660594 J.D.Feramisco, J.L.Goldstein, and M.S.Brown (2004).
Membrane topology of human insig-1, a protein regulator of lipid synthesis.
  J Biol Chem, 279, 8487-8496.  
15028676 M.Hedl, L.Tabernero, C.V.Stauffacher, and V.W.Rodwell (2004).
Class II 3-hydroxy-3-methylglutaryl coenzyme A reductases.
  J Bacteriol, 186, 1927-1932.  
15292254 N.Campobasso, M.Patel, I.E.Wilding, H.Kallender, M.Rosenberg, and M.N.Gwynn (2004).
Staphylococcus aureus 3-hydroxy-3-methylglutaryl-CoA synthase: crystal structure and mechanism.
  J Biol Chem, 279, 44883-44888.
PDB codes: 1tvz 1txt
15247208 R.Doolman, G.S.Leichner, R.Avner, and J.Roitelman (2004).
Ubiquitin is conjugated by membrane ubiquitin ligase to three sites, including the N terminus, in transmembrane region of mammalian 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for sterol-regulated enzyme degradation.
  J Biol Chem, 279, 38184-38193.  
12804701 A.S.Wierzbicki, R.Poston, and A.Ferro (2003).
The lipid and non-lipid effects of statins.
  Pharmacol Ther, 99, 95.  
12621048 L.Tabernero, V.W.Rodwell, and C.V.Stauffacher (2003).
Crystal structure of a statin bound to a class II hydroxymethylglutaryl-CoA reductase.
  J Biol Chem, 278, 19933-19938.
PDB code: 1t02
12815340 M.Machius (2003).
Structural biology: a high-tech tool for biomedical research.
  Curr Opin Nephrol Hypertens, 12, 431-438.  
12606461 S.Bauersachs, H.Blum, S.Mallok, H.Wenigerkind, S.Rief, K.Prelle, and E.Wolf (2003).
Regulation of ipsilateral and contralateral bovine oviduct epithelial cell function in the postovulation period: a transcriptomics approach.
  Biol Reprod, 68, 1170-1177.  
12107122 A.Sutherlin, M.Hedl, B.Sanchez-Neri, J.W.Burgner, C.V.Stauffacher, and V.W.Rodwell (2002).
Enterococcus faecalis 3-hydroxy-3-methylglutaryl coenzyme A synthase, an enzyme of isopentenyl diphosphate biosynthesis.
  J Bacteriol, 184, 4065-4070.  
11842181 J.A.Barbosa, J.Sivaraman, Y.Li, R.Larocque, A.Matte, J.D.Schrag, and M.Cygler (2002).
Mechanism of action and NAD+-binding mode revealed by the crystal structure of L-histidinol dehydrogenase.
  Proc Natl Acad Sci U S A, 99, 1859-1864.
PDB codes: 1k75 1kae 1kah 1kar
11914342 M.Hedl, A.Sutherlin, E.I.Wilding, M.Mazzulla, D.McDevitt, P.Lane, J.W.Burgner, K.R.Lehnbeuter, C.V.Stauffacher, M.N.Gwynn, and V.W.Rodwell (2002).
Enterococcus faecalis acetoacetyl-coenzyme A thiolase/3-hydroxy-3-methylglutaryl-coenzyme A reductase, a dual-function protein of isopentenyl diphosphate biosynthesis.
  J Bacteriol, 184, 2116-2122.  
11921076 R.Zapata, D.Martín, M.D.Piulachs, and X.Bellés (2002).
Effects of hypocholesterolaemic agents on the expression and activity of 3-hydroxy-3-methylglutaryl-CoA reductase in the fat body of the German cockroach.
  Arch Insect Biochem Physiol, 49, 177-186.  
11381031 C.K.Garcia, G.Mues, Y.Liao, T.Hyatt, N.Patil, J.C.Cohen, and H.H.Hobbs (2001).
Sequence diversity in genes of lipid metabolism.
  Genome Res, 11, 1043-1052.  
11349148 E.S.Istvan, and J.Deisenhofer (2001).
Structural mechanism for statin inhibition of HMG-CoA reductase.
  Science, 292, 1160-1164.
PDB codes: 1hw8 1hw9 1hwi 1hwj 1hwk 1hwl
10960099 E.I.Wilding, D.Y.Kim, A.P.Bryant, M.N.Gwynn, R.D.Lunsford, D.McDevitt, J.E.Myers, M.Rosenberg, D.Sylvester, C.V.Stauffacher, and V.W.Rodwell (2000).
Essentiality, expression, and characterization of the class II 3-hydroxy-3-methylglutaryl coenzyme A reductase of Staphylococcus aureus.
  J Bacteriol, 182, 5147-5152.  
11111074 E.S.Istvan, and J.Deisenhofer (2000).
The structure of the catalytic portion of human HMG-CoA reductase.
  Biochim Biophys Acta, 1529, 9.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.