1w6j

From Proteopedia

Jump to: navigation, search

Structure of human OSC in complex with Ro 48-8071

Structural highlights

1w6j is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.2Å
Ligands:BOG, C14, R71
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

LSS_HUMAN Total early-onset cataract;Alopecia-intellectual disability syndrome;Hypotrichosis simplex. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

LSS_HUMAN Key enzyme in the cholesterol biosynthesis pathway. Catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol nucleus (PubMed:14766201, PubMed:7639730, PubMed:26200341). Through the production of lanosterol may regulate lens protein aggregation and increase transparency (PubMed:26200341).[1] [2] [3]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

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[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Loading citation details..
Citations
reviews cite this structure
-1 more
other articles
No citations found

References

  1. ↑ Ruf A, Muller F, D'Arcy B, Stihle M, Kusznir E, Handschin C, Morand OH, Thoma R. The monotopic membrane protein human oxidosqualene cyclase is active as monomer. Biochem Biophys Res Commun. 2004 Mar 5;315(2):247-54. PMID:14766201 doi:10.1016/j.bbrc.2004.01.052
  2. ↑ Zhao L, Chen XJ, Zhu J, Xi YB, Yang X, Hu LD, Ouyang H, Patel SH, Jin X, Lin D, Wu F, Flagg K, Cai H, Li G, Cao G, Lin Y, Chen D, Wen C, Chung C, Wang Y, Qiu A, Yeh E, Wang W, Hu X, Grob S, Abagyan R, Su Z, Tjondro HC, Zhao XJ, Luo H, Hou R, Jefferson J, Perry P, Gao W, Kozak I, Granet D, Li Y, Sun X, Wang J, Zhang L, Liu Y, Yan YB, Zhang K. Lanosterol reverses protein aggregation in cataracts. Nature. 2015 Jul 30;523(7562):607-11. PMID:26200341 doi:10.1038/nature14650
  3. ↑ Baker CH, Matsuda SP, Liu DR, Corey EJ. Molecular cloning of the human gene encoding lanosterol synthase from a liver cDNA library. Biochem Biophys Res Commun. 1995 Aug 4;213(1):154-60. PMID:7639730 doi:http://dx.doi.org/S0006-291X(85)72110-9
  4. ↑ 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. 2004 Nov 4;432(7013):118-22. PMID:15525992 doi:10.1038/nature02993

Contents


PDB ID 1w6j

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/1w6j"
Personal tools