1W6K

Structure of human OSC in complex with Lanosterol

Summary for 1W6K

• Entry DOI: 10.2210/pdb1w6k/pdb
• Related: 1W6J
• Descriptor: LANOSTEROL SYNTHASE, octyl beta-D-glucopyranoside, LANOSTEROL, ... (4 entities in total)
• Functional Keywords: cyclase, cholesterol, lanosterol, monotopic membrane protein, b-octyl-glucoside, isomerase, steroid biosynthesis
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P48449
• Total number of polymer chains: 1
• Total formula weight: 86158.29

Authors

Thoma, R.,Schulz-Gasch, T.,D'Arcy, B.,Benz, J.,Aebi, J.,Dehmlow, H.,Hennig, M.,Ruf, A. (deposition date: 2004-08-19, release date: 2004-10-29, Last modification date: 2024-05-08)

Primary citation

Thoma, R.,Schulz-Gasch, T.,D'Arcy, B.,Benz, J.,Aebi, J.,Dehmlow, H.,Hennig, M.,Stihle, M.,Ruf, A.
Insight Into Steroid Scaffold Formation from the Structure of Human Oxidosqualene Cyclase
Nature, 432:118-, 2004

PubMed 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.

PubMed: 15525992
DOI: 10.1038/NATURE02993

Experimental method

X-RAY DIFFRACTION (2.1 Å)