Team finds dissimilar proteins evolved similar 7-part shape

May 1, 2013
The new research from The Scripps Research Institute shows the smoothened receptor has remarkable structural similarities to genetically unrelated proteins. Credit: Stevens lab, The Scripps Research Institute

Solving the structure of a critical human molecule involved in cancer, scientists at The Scripps Research Institute (TSRI) have found what they call a good example of structural conservation—dissimilar genes that keep very similar shapes.

Described this week in the journal Nature, the work brings attention to what scientists have thought of as a family of called the G protein-coupled receptors (GPCRs). Many GPCRs are important targets for drug design. However, the new work suggests that GPCRs may, in fact, be a subset of a larger group.

"This work highlights the need to modify how we classify the GPCR family," said TSRI Professor Raymond Stevens, PhD, the senior author on the study. "The study suggests we should start calling the family 7-transmembrane receptors, which has been proposed by others before, to better reflect the diversity of the family, both structurally and in terms of function."

The new classification would include proteins with similar shapes to GPCRs—like the smoothened receptor (SMO), which was the subject of the new research.

Different Genes, Same Structure

In the study, the TSRI team solved the high-resolution structure of SMO, which is the first non-class A GPCR structure published to date (class A GPCRs are also known as -like GPCRs). The results showed the molecule is nearly identical to the classic GPCR shape, even though it bears almost no similarity in terms of .

Often, two proteins with very different sequences have different structures, said Chong Wang, a graduate student at TSRI's Kellogg School of Science and Technology who is the first author on the study.

"These receptors are very different—less than 10 percent sequence identity, and yet they have the same 7-transmembrane helical fold," Wang added.

"This is a great example of structural conservation of the 7-transmembrane fold," said TSRI Professor Raymond Stevens, PhD, the senior author on the study. "A key question is, why the magic number 7?"

Potential Target for Drug Design

The work is also significant because the SMO protein itself is a potential target for drug design.

SMO is important for proper growth in the early stages of mammalian development and animals with deficiencies in the activities of this protein develop severe deformities in the womb. The initial discovery was made in 1957, when sheep in Idaho ate corn lily containing cyclopamine and newborns were observed to develop a single eye—a characteristic for which the condition, known as "cyclopia," is named. In work published in the journal Nature in 2000, Stanford University researchers Philip Beachy and Matthew Scott found cyclopamine inhibits the SMO receptor.

The body reduces its need for SMO in adulthood, and its activity is usually curtailed. However, later in life the protein can also play a role in disease, this time by helping cancerous tumors grow. SMO receptor inhibition has been harnessed as a means to reduce basal cell carcinoma, a common form of skin cancer.

The discovery of the structure of SMO may help researchers develop new molecules to treat cancer and other diseases.

"The structure of the human smoothened receptor bound to an anti-cancer compound will help us understand the receptor's role in cancer, as well as its role in the normal process of embryonic development," said Jean Chin, PhD, of the National Institutes of Health's National Institute of General Medical Sciences, which partly supported the research. "In addition, comparison of smoothened's unique structure with those of the more conventional GPCRs will teach us a lot about how these receptors respond to the many therapeutics they interact with."

Explore further: Study reveals how serotonin receptors can shape drug effects from LSD to migraine medication

More information: The Nature article, "Structure of the human smoothened receptor bound to an antitumor agent," was authored by Chong Wang, Huixian Wu, Vsevolod Katritch, Gye Won Han, Xi-Ping Huang, Wei Liu, Fai Yiu Siu, Bryan L. Roth, Vadim Cherezov and Raymond C. Stevens. dx.doi.org/10.1038/nature12167

Related Stories

Study reveals how serotonin receptors can shape drug effects from LSD to migraine medication

March 21, 2013
A team including scientists from The Scripps Research Institute (TSRI), the University of North Carolina at Chapel Hill and the Chinese Academy of Sciences has determined and analyzed the high-resolution atomic structures ...

Scientists provide detailed view of brain protein structure: Results may help improve drugs for neurological disorders

October 10, 2012
Researchers have published the first highly detailed description of how neurotensin, a neuropeptide hormone which modulates nerve cell activity in the brain, interacts with its receptor. Their results suggest that neuropeptide ...

Recommended for you

Age and gut bacteria contribute to multiple sclerosis disease progression

November 17, 2017
Researchers at Rutgers Robert Wood Johnson Medical School published a study suggesting that gut bacteria at young age can contribute to multiple sclerosis (MS) disease onset and progression.

Molecular guardian defends cells, organs against excess cholesterol

November 16, 2017
A team of researchers at the Harvard T. H. Chan School of Public Health has illuminated a critical player in cholesterol metabolism that acts as a molecular guardian in cells to help maintain cholesterol levels within a safe, ...

Ancient enzyme could boost power of liquid biopsies to detect and profile cancers

November 16, 2017
Scientists are developing a set of medical tests called liquid biopsies that can rapidly detect the presence of cancers, infectious diseases and other conditions from only a small blood sample. Researchers at The University ...

Prototype ear plug sensor could improve monitoring of vital signs

November 16, 2017
Scientists have developed a sensor that fits in the ear, with the aim of monitoring the heart, brain and lungs functions for health and fitness.

FDA to crack down on risky stem cell offerings

November 16, 2017
U.S. health authorities announced plans Thursday to crack down on doctors pushing stem cell procedures that pose the gravest risks to patients amid an effort to police a burgeoning medical field that previously has received ...

Strain of intestinal bacteria can stop high-salt diet from inducing inflammatory response linked to hypertension

November 15, 2017
Microbes living in your gut may help protect against the effects of a high-salt diet, according to a new study from MIT.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.