Revealing the architecture of the human sugar sensor

Our attraction for sugar has increased to an unhealthy level. The average man in the United States now consumes more than 100 pounds of sweet each year, from 18 kg in 1800.

With the new study published on May 7 at Cell, scientists at the University of Columbia took a significant step towards tackling this crisis of public health. For the first time, they have mapped the 3-D structure of the human sweet taste, the molecular machine that allows us to try sweet things. This could lead to the discovery of new receptor regulatory principles that would significantly change the attraction and appetite for sugar.

The leading role played by sugar in obesity cannot be overlooked. The artificial sweeteners we use today to replace sugar simply do not meaningfully change our desire for sugar. Now that we know what the receptor looks like, we may be able to design something better. ”

Juen Zhang, PhD, co-authored study author, postdoctoral collaborator at the Laboratory

Sweet receptors in our tongue can detect a large number of different chemicals that have a sweet taste, from common table sugar (also known as sucrose) in antimicrobial enzymes in chicken eggs. Unlike other receptors for bitter, sour or other tastes-our sweet sensors have evolved so that they are not very sensitive. This helps us to focus on sugar -rich foods for energy and leads the need for many sweets to satisfy our sweet tooth.

Determining the structure of human sweet receptor is the key to understanding how it helps us detect sweet taste, fundamentally promoting understanding the perception of taste. More than 20 years ago, Dr. Zuker and his colleagues revealed the genes behind the mammalian sweet flavor receptor. This landmark project revealed its chemical formula, but so far no one knew its exact shape, as well as how knowledge of the cake recipe would not tell you what the dough would look like when it was over.

Without this knowledge, understanding the molecular base of sweet detection in rational designs ways to regulate the functioning of this basic receptor was a challenge, Dr. Zuker said, in whose workshop this new work was carried out.

“All the artificial sweeteners we use today were either discovered randomly or based on well-known sweet tasty molecules,” said co-writer Brian Wang, a research assistant at the Zuker Laboratory. “As a result, most artificial sweeteners have disadvantages.”

The new work maps the structure of the human sweet taste in unprecedented detail, in a analysis as good as 2.8 Angstroms. Compared, the smaller person, the hydrogen, is slightly more than 1 Angstrom wide.

Researchers took innovative approaches and about three years to map the structure of the sweet receptor, to a large extent because it has been difficult to develop this protein in cells in laboratory dishes.

“Just getting the cleaned protein we needed to map the structure needed more than 150 different preparations over three years,” said co-author Zhengyuan Lu, a doctoral student at the Zuker workshop.

The scientists then used Cryo-Em-Electron microscopy to analyze the human sweet taste. This technical electron beam fires in molecules that have been frozen in solution, helping researchers capture snapshots of these molecules from different angles, from which they can rebuild their three -dimensional structures at the individual level.

Of particular importance, Cryo-Em revealed the receptor’s pocket: the cavity where sweet things stick and activate all the reactions that lead our strong appetite to sweets.

“Defining the pocket of this receptor is very accurate is very vital to understanding its function,” said co-author of the study Anthony Fitzpatrick, PhD, main researcher at the Columbia Institute Zuckerman. “Knowing its exact shape, we can see why sweeteners are associated with it and how to make or find better molecules that activate the receptor or regulate its operation,” added Dr. Fitzpatrick, who is also an assistant professor of biochemistry and molecular biophysics at Columbia Columbia College of Physicians.

The Human Sweet Taste Human Receiver consists of two main half. One of them, called Tas1R2, features the pocket of commitment, an ingredient that looks like a venus Flytrap. Knowing the structure of this part can also help us understand why people differ in how sensitive sweets are.

Scientists mapped the structure of the receptor as it is bound to two of the most commonly used artificial sweeteners, aspartame and saccate. These are, respectively, 200 and 600 times sweeter than sucrose.

The researchers then systematically changed tiny sections of the receptor. This has helped to shed light on the role that each of these places plays a commitment to sweeteners, said co-author of the study Ruihuan Yu, a doctoral student at the Zuker laboratory.

“We are trying to understand science forward so that we can help people,” said the co-author of the study Andrew Chang, a research technician in the Fitzpatrick lab.

Although the human receptor of sweet taste is mainly in taste in the mouth, Dr. Zhang noted that it is also scattered throughout the body, where it can play a role in the functioning of organs such as the pancreas. Therefore, the new map of the structure of this receptor can support the research that investigates our metabolism, as well as in disorders such as diabetes.