Nature Structural Biology pp 499 - 504 and pp 476 - 478

While cholesterol is required for normal health, too much of it can be deadly. Along with high blood pressure and cigarette smoking, it is one of the three major risk factors for heart disease. More than half of all adult Americans have a blood cholesterol level that is higher than 'desirable.'

The problem with too much blood cholesterol is that over time it can build up in the walls of your arteries (a process called atherosclerosis) and can slow or block the flow of blood to your heart. Among many things, blood carries a constant supply of oxygen to the heart. Without oxygen, heart muscle weakens, resulting in chest pain, heart attacks, or even death.

There are two types of cholesterol - 'good' and 'bad'. Actually these descriptions refer to the lipoproteins that carry cholesterol throughout the body. 'Good' cholesterol is associated with high density lipoproteins (HDLs) that remove excess cholesterol from the body by transporting it to the liver where it is disposed of. 'Bad' cholesterol is associated with low density lipoproteins (LDLs). Getting cholesterol into cells requires the LDL receptor. Normally, the LDL receptor keeps the cholesterol level in balance. If the receptor malfunctions then cholesterol levels can skyrocket.

While most of us can control our blood cholesterol levels by following a diet that is low in saturated fat and cholesterol, a small percentage of people cannot. About 7 out of 1000 people suffer from familial hypercholesterolemia (FH). FH is an inherited genetic disease that is marked by high cholesterol levels and an increased risk of heart disease. Currently, there are more than 600 mutations in the LDL receptor gene that give rise to FH.

The LDL receptor consists of several parts or domains that must form and interact properly to function. One region of the receptor is crucial for the release of bound LDL. By solving the X-ray crystal structure of this part of the LDL receptor, Blacklow and colleagues at Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, have gained a more detailed understanding of how mutations in this part of the receptor lead to disease. They find that many of the mutations seem to affect either the folding of the individual domains within this part of the receptor or the interaction between these domains. These studies are an important step in understanding how the LDL receptor functions normally as well as how mutations in the receptor cause it to go awry.

Joachim Herz at the University of Texas Southwestern Medical Center, Dallas, Texas, USA, discusses these findings in an accompanying News and Views report.

Nature Structural Biology pp 505 - 509

People under constant stress worry about stomach ulcers. This is because of the general belief that ulcers are caused by excess acid in the stomach associated with emotional stress and diets that include spicy foods. The discovery ~20 years ago of a bacterium called Helicobacter pylori in the stomachs of ulcer patients challenged this view. Since then, the significant correlation between the symptoms of ulcers and the presence of these bacteria in the stomach has established H. pylori as the major cause of upper digestive tract disease such as severe chronic gastritis and stomach ulcers.

Because of the high acid concentration, the stomach is a hostile environment for most bacteria. To inhabit such an environment, H. pylori produces large amounts of a very active enzyme called urease, which produces ammonia to neutralize the acid in the immediate vicinity of the bacteria. To understand how the H. pylori urease remains active under acidic conditions in the stomach, Oh and colleagues at Pohang University of Science and Technology, Pohang, Kyungbuk, Korea have determined the crystal structure of the enzyme.

The H. pylori urease consists of 12 catalytic units, the structure of which is similar to that of ureases from other microorganisms. However, the 12 units form a spherical assembly with an internal cavity, and the active sites of the units are clustered in this supramolecular architecture. Moreover, the authors demonstrated that the clustered active sites are important for providing resistance against acid inactivation. These results suggest a mechanism by which H. pylori urease are protected in the stomach, and more importantly, how this enzyme could be a target for treating H. pylori infection.

Bruce E. Dunn at the Milwaukee Veteran Administration Medical Center, Milwaukee, Wisconsin, USA discusses these results in an associated News and Views and the History piece concerns the discovery of H. pylori as the causative agent.