1w6j

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spinqualitylabelsall models 1w6j, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

STRUCTURE OF HUMAN OSC IN COMPLEX WITH RO 48-8071

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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.

Disease

Known disease associated with this structure: Osteopathia striata with cranial sclerosis OMIM:[300373]

About this Structure

1W6J is a Single protein structure of sequence from Homo sapiens with BOG, R71 and C14 as ligands. Active as Lanosterol synthase, with EC number 5.4.99.7 Known structural/functional Site: . 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

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