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Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase


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 reaction1,2. 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 statins3. 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.

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Figure 1: Ribbon diagram of human OSC.
Figure 2: OSC catalyses the conversion of 2,3-oxidosqualene 1 to lanosterol 2.
Figure 3: Cyclization mechanism in the light of the OSC–lanosterol complex structure.
Figure 4: OSC residues interacting with the inhibitor Ro 48-8071 in the crystal structure.


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We thank the staff at the beamline X06SA at the Swiss Light Source (SLS, Switzerland) for support, and C. Vonrhein (Global Phasing Ltd) for an early version of autoBUSTER. We thank all colleagues at Roche Basel for support, and especially O. Morand for discussions.

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Correspondence to Armin Ruf.

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Supplementary Table 1

Data collection and refinement statistics. (DOC 2642 kb)

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Thoma, R., Schulz-Gasch, T., D'Arcy, B. et al. Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase. Nature 432, 118–122 (2004).

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