Scientists paint new picture of dance between protein and binding partners

January 10, 2012

Using a blend of technologies, scientists from the Florida campus of The Scripps Research Institute have painted a new picture of how biochemical information can be transmitted through the modification of a protein. Previously, scientists believed that during the pairing of proteins and their binding partners ("ligands"), proteins modified their shape while ligands remained stable. The new study shows this one-size-fits-all solution is not entirely accurate.

Instead, the situation resembles a kind of complex but carefully organized dance routine, where the ligand samples a variety of binding modes while the protein also modifies its shape, a process that results in their pairing and changes in the critical for its function.

These new findings, published in the January 11, 2012 edition of the journal Structure, could affect future drug design.

"Using a , we gleaned something from our data that no one else has," said Douglas Kojetin, an assistant professor on the Scripps Florida campus who led the study. "The conventional wisdom is that bind in one orientation but our study shows that they can bind in multiple modes. That means if we can optimize a ligand to bind in mode B rather than mode A, we might be able to select the therapeutic results we want."

The new study—which used a number of complementary technologies including NMR spectroscopy and hydrogen/deuterium exchange (HDX) coupled to mass spectrometery, combined with previous x-ray crystallography analyses—provides detailed insights into the real-time actions of molecules that could never be determined with a single technology.

Specifically, the researchers revealed insights into ligand and receptor dynamics in the nuclear receptor known as PPARγ (peroxisome-proliferator-activated receptor). PPARγ has been implicated in metabolic diseases including obesity, diabetes, and atherosclerosis.

The study also found that various gradations in these ligands influence the dynamics of this exchange, adding another layer of complexity. "One of the compounds, MRL24, binds to the receptor and has anti-diabetic efficacy, but doesn't activate it very well," Kojetin said. "This is what you want because when the receptor is activated you get side effects such as weight gain and brittle bones."

"This study in particular highlights the importance of multidisciplinary collaborative efforts to truly understand the molecular details of drug-receptor interactions", says Kojetin. "This work is an excellent example of the strong campus collaborations we have with the laboratories of Patrick Griffin, Thomas Burris, and Theodore Kamenecka."

Explore further: Scientists reveal first structure of a class of proteins that help guide blood cell movement

More information: The first author of the study, "Ligand and Receptor Dynamics Contribute to the Mechanism of Graded PPAR γ Agonism," is Travis S. Hughes of Scripps Research. Other authors include Michael J. Chalmers, Scott Novick, Dana S. Kuruvilla, Mi Ra Chang, Theodore M. Kamenecka ,Thomas P. Burris, and Patrick R. Griffin of Scripps Research; Mark Rance of the University of Cincinnati; and Bruce A. Johnson of One Moon Scientific Inc.

Related Stories

Researchers discover how natural drug fights inflammation

December 9, 2010

Researchers at the Virginia Bioinformatics Institute at Virginia Tech have discovered how abscisic acid, a natural plant hormone with known beneficial properties for the treatment of disease, helps fight inflammation. The ...

Scientists uncover new DNA role in modifying gene function

April 10, 2011

For years, scientists have thought of DNA as a passive blueprint capable only of producing specific proteins through RNA transcription. Now, research led by scientists from the Florida campus of The Scripps Research Institute ...

Recommended for you

Brazilian wasp venom kills cancer cells by opening them up

September 1, 2015

The social wasp Polybia paulista protects itself against predators by producing venom known to contain a powerful cancer-fighting ingredient. A Biophysical Journal study published September 1 reveals exactly how the venom's ...

Water heals a bioplastic

September 1, 2015

A drop of water self-heals a multiphase polymer derived from the genetic code of squid ring teeth, which may someday extend the life of medical implants, fiber-optic cables and other hard to repair in place objects, according ...

Naturally-occurring protein enables slower-melting ice cream

August 31, 2015

(Phys.org)—Scientists have developed a slower-melting ice cream—consider the advantages the next time a hot summer day turns your child's cone with its dream-like mound of orange, vanilla and lemon swirls with chocolate ...

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.