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PDBsum entry 1w6k

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Isomerase PDB id
1w6k
Jmol
Contents
Protein chain
725 a.a. *
Ligands
BOG ×8
LAN
Waters ×963
* Residue conservation analysis
PDB id:
1w6k
Name: Isomerase
Title: Structure of human osc in complex with lanosterol
Structure: Lanosterol synthase. Chain: a. Synonym: oxidosqualene--lanosterol cyclase, oxido squalene cyclase, 2,3-epoxysqualene--lanosterol cyclase, osc. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: pichia pastoris. Expression_system_taxid: 4922.
Resolution:
2.10Å     R-factor:   0.147     R-free:   0.188
Authors: R.Thoma,T.Schulz-Gasch,B.D'Arcy,J.Benz,J.Aebi,H.Dehmlow, M.Hennig,A.Ruf
Key ref:
R.Thoma et al. (2004). Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase. Nature, 432, 118-122. PubMed id: 15525992 DOI: 10.1038/nature02993
Date:
19-Aug-04     Release date:   29-Oct-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P48449  (ERG7_HUMAN) -  Lanosterol synthase
Seq:
Struc:
 
Seq:
Struc:
732 a.a.
725 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.5.4.99.7  - Lanosterol synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Lanosterol and Cycloartenol Biosynthesis
      Reaction: (3S)-2,3-epoxy-2,3-dihydrosqualene = lanosterol
(3S)-2,3-epoxy-2,3-dihydrosqualene
=
lanosterol
Bound ligand (Het Group name = LAN)
corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   4 terms 
  Biological process     small molecule metabolic process   5 terms 
  Biochemical function     catalytic activity     4 terms  

 

 
    Key reference    
 
 
DOI no: 10.1038/nature02993 Nature 432:118-122 (2004)
PubMed id: 15525992  
 
 
Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase.
R.Thoma, T.Schulz-Gasch, B.D'Arcy, J.Benz, J.Aebi, H.Dehmlow, M.Hennig, M.Stihle, A.Ruf.
 
  ABSTRACT  
 
In higher organisms the formation of the steroid scaffold is catalysed exclusively by the membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase). In a highly selective cyclization reaction OSC forms lanosterol with seven chiral centres starting from the linear substrate 2,3-oxidosqualene. Valuable data on the mechanism of the complex cyclization cascade have been collected during the past 50 years using suicide inhibitors, mutagenesis studies and homology modelling. Nevertheless it is still not fully understood how the enzyme catalyses the reaction. Because of the decisive role of OSC in cholesterol biosynthesis it represents a target for the discovery of novel anticholesteraemic drugs that could complement the widely used statins. Here we present two crystal structures of the human membrane protein OSC: the target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors. The complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.
 
  Selected figure(s)  
 
Figure 2.
Figure 2: OSC catalyses the conversion of 2,3-oxidosqualene 1 to lanosterol 2. The initial substrate chair -boat -chair conformation of 2,3-oxidosqualene 1, putative conformations after A-ring, B-ring and C-ring closure (2,3-oxidosqualene cation numbering), and skeletal rearrangement of protosterol cation (lanosterol cation numbering) through 1,2-shifts of hydride and methyl groups are shown.
Figure 3.
Figure 3: Cyclization mechanism in the light of the OSC -lanosterol complex structure. a, Stereo view of the autoBUSTER difference electron density contoured at 3 . Residues at a distance less than 5 are shown. Water molecules are observed only near Asp 455 and His 232. b, A- and B-rings: cation - interactions of Trp 387, Phe 444 and Trp 581 can stabilize the cyclization intermediates positively charged at oxidosqualene positions 6 and 10. The catalytic acid Asp 455 is activated by Cys 456 and Cys 533. The Tyr 98 side chain sterically hinders the B-ring from assuming the favourable chair conformation. c, C- and D-rings: Phe 696 and the His 232 can stabilize the positive charge at the C-20 protosterol cation by cation - interactions. His 232 is the nearest basic residue that could deprotonate the C-8/C-9 lanosterol cation.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2004, 432, 118-122) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21160477 M.Köksal, Y.Jin, R.M.Coates, R.Croteau, and D.W.Christianson (2011).
Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis.
  Nature, 469, 116-120.
PDB codes: 3p5p 3p5r
21377465 S.Sawai, H.Uchiyama, S.Mizuno, T.Aoki, T.Akashi, S.Ayabe, and T.Takahashi (2011).
Molecular characterization of an oxidosqualene cyclase that yields shionone, a unique tetracyclic triterpene ketone of Aster tataricus.
  FEBS Lett, 585, 1031-1036.  
21315634 S.Z.Grinter, Y.Liang, S.Y.Huang, S.M.Hyder, and X.Zou (2011).
An inverse docking approach for identifying new potential anti-cancer targets.
  J Mol Graph Model, 29, 795-799.  
21157613 T.K.Wu, Y.C.Chang, Y.T.Liu, C.H.Chang, H.Y.Wen, W.H.Li, and W.S.Shie (2011).
Mutation of isoleucine 705 of the oxidosqualene-lanosterol cyclase from Saccharomyces cerevisiae affects lanosterol's C/D-ring cyclization and 17α/β-exocyclic side chain stereochemistry.
  Org Biomol Chem, 9, 1092-1097.  
21098670 F.Y.Lin, C.I.Liu, Y.L.Liu, Y.Zhang, K.Wang, W.Y.Jeng, T.P.Ko, R.Cao, A.H.Wang, and E.Oldfield (2010).
Mechanism of action and inhibition of dehydrosqualene synthase.
  Proc Natl Acad Sci U S A, 107, 21337-21342.
PDB codes: 3acw 3acx 3acy 3adz 3ae0 3lgz 3npr 3nri
20304090 P.D.Kiser, and K.Palczewski (2010).
Membrane-binding and enzymatic properties of RPE65.
  Prog Retin Eye Res, 29, 428-442.  
20602361 R.Cao, Y.Zhang, F.M.Mann, C.Huang, D.Mukkamala, M.P.Hudock, M.E.Mead, S.Prisic, K.Wang, F.Y.Lin, T.K.Chang, R.J.Peters, and E.Oldfield (2010).
Diterpene cyclases and the nature of the isoprene fold.
  Proteins, 78, 2417-2432.  
20956302 R.R.Knowles, and E.N.Jacobsen (2010).
Attractive noncovalent interactions in asymmetric catalysis: links between enzymes and small molecule catalysts.
  Proc Natl Acad Sci U S A, 107, 20678-20685.  
20861902 T.Itoh, K.Tokunaga, Y.Matsuda, I.Fujii, I.Abe, Y.Ebizuka, and T.Kushiro (2010).
Reconstitution of a fungal meroterpenoid biosynthesis reveals the involvement of a novel family of terpene cyclases.
  Nat Chem, 2, 858-864.  
19037261 A.Pearson, and D.B.Rusch (2009).
Distribution of microbial terpenoid lipid cyclases in the global ocean metagenome.
  ISME J, 3, 352-363.  
19469579 F.R.Pinacho Crisóstomo, A.Lledó, S.R.Shenoy, T.Iwasawa, and J.Rebek (2009).
Recognition and organocatalysis with a synthetic cavitand receptor.
  J Am Chem Soc, 131, 7402-7410.  
19207562 T.Frickey, and E.Kannenberg (2009).
Phylogenetic analysis of the triterpene cyclase protein family in prokaryotes and eukaryotes suggests bidirectional lateral gene transfer.
  Environ Microbiol, 11, 1224-1241.  
18061922 A.Fürstner, and A.Korte (2008).
Total synthesis of epohelmin B and its analogues.
  Chem Asian J, 3, 310-318.  
18249199 D.W.Christianson (2008).
Unearthing the roots of the terpenome.
  Curr Opin Chem Biol, 12, 141-150.  
18389131 J.F.Zhao, Y.J.Zhao, and T.P.Loh (2008).
Indium tribromide-promoted arene-terminated epoxy olefin cyclization.
  Chem Commun (Camb), (), 1353-1355.  
18436644 T.Bosak, R.M.Losick, and A.Pearson (2008).
A polycyclic terpenoid that alleviates oxidative stress.
  Proc Natl Acad Sci U S A, 105, 6725-6729.  
17964172 T.Korosec, J.Acimovic, M.Seliskar, D.Kocjan, K.F.Tacer, D.Rozman, and U.Urleb (2008).
Novel cholesterol biosynthesis inhibitors targeting human lanosterol 14alpha-demethylase (CYP51).
  Bioorg Med Chem, 16, 209-221.  
17603894 A.L.Lomize, I.D.Pogozheva, M.A.Lomize, and H.I.Mosberg (2007).
The role of hydrophobic interactions in positioning of peripheral proteins in membranes.
  BMC Struct Biol, 7, 44.  
17686016 A.Pearson, S.R.Flood Page, T.L.Jorgenson, W.W.Fischer, and M.B.Higgins (2007).
Novel hopanoid cyclases from the environment.
  Environ Microbiol, 9, 2175-2188.  
17925399 A.Villagra, N.Ulloa, X.Zhang, Z.Yuan, E.Sotomayor, and E.Seto (2007).
Histone deacetylase 3 down-regulates cholesterol synthesis through repression of lanosterol synthase gene expression.
  J Biol Chem, 282, 35457-35470.  
18033581 I.Abe (2007).
Enzymatic synthesis of cyclic triterpenes.
  Nat Prod Rep, 24, 1311-1331.  
17186944 M.M.Beyea, C.L.Heslop, C.G.Sawyez, J.Y.Edwards, J.G.Markle, R.A.Hegele, and M.W.Huff (2007).
Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in macrophages through increased endogenous synthesis of 24(S),25-epoxycholesterol.
  J Biol Chem, 282, 5207-5216.  
17154325 S.Oliaro-Bosso, F.Viola, S.Taramino, S.Tagliapietra, A.Barge, G.Cravotto, and G.Balliano (2007).
Inhibitory Effect of Umbelliferone Aminoalkyl Derivatives on Oxidosqualene Cyclases from S. cerevisiae, T. cruzi, P. carinii, H. sapiens, and A. thaliana: a Structure-Activity Study.
  ChemMedChem, 2, 226-233.  
17457817 S.Prisic, J.Xu, R.M.Coates, and R.J.Peters (2007).
Probing the role of the DXDD motif in Class II diterpene cyclases.
  Chembiochem, 8, 869-874.  
16527957 D.W.Christianson (2006).
Biochemistry. Five golden rings.
  Science, 311, 1382-1383.  
16425307 Q.Xiong, W.K.Wilson, and S.P.Matsuda (2006).
An Arabidopsis oxidosqualene cyclase catalyzes iridal skeleton formation by Grob fragmentation.
  Angew Chem Int Ed Engl, 45, 1285-1288.  
16754609 R.E.Summons, A.S.Bradley, L.L.Jahnke, and J.R.Waldbauer (2006).
Steroids, triterpenoids and molecular oxygen.
  Philos Trans R Soc Lond B Biol Sci, 361, 951-968.  
16446812 S.P.Matsuda, W.K.Wilson, and Q.Xiong (2006).
Mechanistic insights into triterpene synthesis from quantum mechanical calculations. Detection of systematic errors in B3LYP cyclization energies.
  Org Biomol Chem, 4, 530-543.  
15929157 K.U.Wendt (2005).
Enzyme mechanisms for triterpene cyclization: new pieces of the puzzle.
  Angew Chem Int Ed Engl, 44, 3966-3971.  
16196424 M.Ceruti, G.Balliano, F.Rocco, A.Lenhart, G.E.Schulz, F.Castelli, and P.Milla (2005).
Synthesis and biological activity of new iodoacetamide derivatives on mutants of squalene-hopene cyclase.
  Lipids, 40, 729-735.  
16120615 M.Germann, C.Gallo, T.Donahue, R.Shirzadi, J.Stukey, S.Lang, C.Ruckenstuhl, S.Oliaro-Bosso, V.McDonough, F.Turnowsky, G.Balliano, and J.T.Nickels (2005).
Characterizing sterol defect suppressors uncovers a novel transcriptional signaling pathway regulating zymosterol biosynthesis.
  J Biol Chem, 280, 35904-35913.  
16035021 S.Ma, P.Lu, L.Lu, H.Hou, J.Wei, Q.He, Z.Gu, X.Jiang, and X.Jin (2005).
What can a metal catalyst do with allenes? One-step formation of steroid scaffolds from readily available starting materials.
  Angew Chem Int Ed Engl, 44, 5275-5278.  
16477810 S.Oliaro-Bosso, M.Ceruti, G.Balliano, P.Milla, F.Rocco, and F.Viola (2005).
Analogs of squalene and oxidosqualene inhibit oxidosqualene cyclase of Trypanosoma cruzi expressed in Saccharomyces cerevisiae.
  Lipids, 40, 1257-1262.  
16235265 S.Oliaro-Bosso, T.Schulz-Gasch, G.Balliano, and F.Viola (2005).
Access of the substrate to the active site of yeast oxidosqualene cyclase: an inhibition and site-directed mutagenesis approach.
  Chembiochem, 6, 2221-2228.  
16106294 T.Abe, and T.Hoshino (2005).
Enzymatic cyclizations of squalene analogs with threo- and erythro-diols at the 6,7- or 10,11-positions by recombinant squalene cyclase. Trapping of carbocation intermediates and mechanistic insights into the product and substrate specificities.
  Org Biomol Chem, 3, 3127-3139.  
15915534 T.K.Wu, Y.T.Liu, and C.H.Chang (2005).
Histidine residue at position 234 of oxidosqualene-lanosterol cyclase from saccharomyces cerevisiae simultaneously influences cyclization, rearrangement, and deprotonation reactions.
  Chembiochem, 6, 1177-1181.  
15691023 S.Oliaro-Bosso, F.Viola, S.Matsuda, G.Cravotto, S.Tagliapietra, and G.Balliano (2004).
Umbelliferone aminoalkyl derivatives as inhibitors of oxidosqualene cyclases from Saccharomyces cerevisiae, Trypanosoma cruzi, and Pneumocystis carinii.
  Lipids, 39, 1007-1012.  
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.