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PDB:1W6J

Protein Name

Lanosterol synthase

Species

Homo sapiens (human)

Biological Context

Hormones are peptide or steroid substances which regulate physiological activities like growth and metabolism. Steroid hormones include such important ones like the sex hormones estrogen and progesterone, produced by the ovaries, and testosterone, produced by the testis. Ecdysone, an insect hormone that triggers the metamorphosis of larvae to adults is also a steroid. All steroid hormones are synthesized from cholesterol. Cholesterol is a soft, fat-like substance that can be found in the blood and all the cells. The body either produces it itself or gets it from the animal products that we eat - meat, fish, eggs, milk. Cholesterol cannot be dissolved in the blood. It has to be transported to and from the cells by special carriers, lipoproteins . The low-density lipoproteins, LDL, are known as "bad cholesterol" because large amounts of them in the blood stream can clog the arteries and increase the risks of heart-attack and stroke. On the other hand, HDL, or high-density lipoproteins, are called "good cholesterol" because they transport cholesterol from the tissues back to the liver where it is secreted in the bile. Therefore low concentrations of LDL and high concentrations of HDL are desirable for a healthy life. The biosynthesis of cholesterol and subsequent steroids starts with a conversion of (S)-2,3 oxidosqualene to lanosterol. This process is catalyzed by the membrane protein OxidoSqualene Cyclase, OSC ( or sometimes referred to as Lanosterol Synthase). Inhibition of this protein may help to lower the cholesterol levels in the blood.

Structure Description

1w6j1w6j_x1w6j_y

Here we can see the structure of the enzyme with an inhibitor, Ro 48-8071. OSC is a membrane protein which is partially buried in the membrane but does not extend through it . Such proteins are called monotopic . It has two large alpha-helical domains and three smaller beta-sheet assemblies connected by loops. The active site of the enzyme is located between the two alpha-domains. It can be accessed by two channels - one polar leading to the enzyme surface , and one hydrophobic which exits into the non-polar half of the bilayer. After an oxidosqualene molecule enters the cavity, it adopts a so-called "chair-boat-chair" conformation . Then its epoxide ring is protonated . This is followed by a number of new ring formations and conformational changes leading to the final product - a lanosterol molecule. OSC controls this process by stabilizing the intermediates. But how does the inhibitor work? Ro 48-8071 contains a basic nitrogen. Its proton forms a strong hydrogen bond with an aspartic acid residue, located half-way through the polar channel. The same amino group "sticks" even tighter to the protein by forming cation-pi-bonds with surrounding aromatic rings of phenylalanine and tryptophan amino acids . In addition, the bromine atom of the inhibitor is also firmly immobilized by interactions with tyrosine , isoleucine and cysteine residues. For optimal function, the molecule of an inhibitor has to fit perfectly, not only in size but also with respect to its chemical characteristics into the cavity environment of the enzyme channel. This crystal structure gives us an invaluable template for the creation of new cholesterol lowering drugs.

Protein Data Bank (PDB)

References

Source

  • 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) 432:118-122 PubMed:15525992.

Others

author: Rossen Apostolov


Japanese version:PDB:1W6J