1w6j
From Proteopedia
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|PDB= 1w6j |SIZE=350|CAPTION= <scene name='initialview01'>1w6j</scene>, resolution 2.20Å | |PDB= 1w6j |SIZE=350|CAPTION= <scene name='initialview01'>1w6j</scene>, resolution 2.20Å | ||
|SITE= <scene name='pdbsite=AC1:Bog+Binding+Site+For+Chain+A'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Bog+Binding+Site+For+Chain+A'>AC1</scene> | ||
| - | |LIGAND= <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=R71:[4-({6-[ALLYL(METHYL)AMINO]HEXYL}OXY)-2-FLUOROPHENYL](4-BROMOPHENYL)METHANONE'>R71</scene> | + | |LIGAND= <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=C14:TETRADECANE'>C14</scene>, <scene name='pdbligand=R71:[4-({6-[ALLYL(METHYL)AMINO]HEXYL}OXY)-2-FLUOROPHENYL](4-BROMOPHENYL)METHANONE'>R71</scene> |
| - | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Lanosterol_synthase Lanosterol synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.4.99.7 5.4.99.7] </span> | |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1w6j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1w6j OCA], [http://www.ebi.ac.uk/pdbsum/1w6j PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1w6j RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
| - | |||
| - | ==Disease== | ||
| - | Known disease associated with this structure: Osteopathia striata with cranial sclerosis OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300373 300373]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Schulz-Gasch, T.]] | [[Category: Schulz-Gasch, T.]] | ||
[[Category: Thoma, R.]] | [[Category: Thoma, R.]] | ||
| - | [[Category: BOG]] | ||
| - | [[Category: C14]] | ||
| - | [[Category: R71]] | ||
[[Category: b-octyl-glucoside]] | [[Category: b-octyl-glucoside]] | ||
[[Category: cholesterol]] | [[Category: cholesterol]] | ||
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[[Category: steroid biosynthesis]] | [[Category: steroid biosynthesis]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:31:51 2008'' |
Revision as of 21:31, 30 March 2008
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| , resolution 2.20Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | , , | ||||||
| Activity: | Lanosterol synthase, with EC number 5.4.99.7 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
STRUCTURE OF HUMAN OSC IN COMPLEX WITH RO 48-8071
Overview
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.
About this Structure
1W6J is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase., Thoma R, Schulz-Gasch T, D'Arcy B, Benz J, Aebi J, Dehmlow H, Hennig M, Stihle M, Ruf A, Nature. 2004 Nov 4;432(7013):118-22. PMID:15525992
Page seeded by OCA on Mon Mar 31 00:31:51 2008
