Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists Find Dissimilar Proteins Evolved Similar 7-Part Shape

03.05.2013
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 molecules 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.


Image courtesy of the Stevens lab, The Scripps Research Institute.

The new research shows the smoothened receptor (SMO) has remarkable structural similarities to genetically unrelated proteins.

“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 rhodopsin-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 genetic sequence.

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 Stevens. “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.”

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. For more information, see: http://dx.doi.org/10.1038/nature12167

This work was funded by the National Institutes of Health through grant numbers P50 GM073197, U54 GM094618, F32 DK088392, R01 MH61887, U19 MH82441 and R01 DA27170. Additional support was provided through the National Institute of Mental Health Psychoactive Drug Screening Program and the Michael Hooker Chair of Pharmacology to Bryan Roth at the University of North Carolina.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

Mika Ono | Newswise
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>