New DNA role in the change by Scripps Research scientists discovered gene function

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For years, scientists DNA as passive blueprint location have thought only specific proteins by RNA transcription. Now, research under the direction of the Florida campus of Scripps scientists can Research Institute, DNA has called shown core receptors also for the fine tuning of the activity of certain proteins.

These new findings can allow design therapies to the specific genes very specifically in a number of important diseases including osteoporosis, obesity, autoimmune disease and cancer could enable.

The study was published in the journal nature structural & molecular biology 10 April 2011.

"This study provides for what we now recognize as critically important activities the first evidence," said team leader Patrick R. Griffin, PhD, Chairman of the Department of molecular therapeutics and Director of Translational Research Institute at Scripps Florida. "This new understanding could lead to the development of ways to promote the very goal-oriented activity, that is exactly what you need to produce safe and effective therapies."

The new study focuses on the interactions between a protein complex consisting of the vitamin D receptor and vitamin a X receptor and its ligands, vitamin D and 9-CIS Retinoic acid (a metabolite of vitamin A), and DNA, and a co-regulation protein. Receptors are proteins, which one or bind several specific types of signaling molecules.

Scientists worked together on this study to understand how vitamin D works at the very simplest level, given the fact that vitamin D plays an important role in bone health and thus on its research platform for osteoporosis is at Eli Lilly and company.

"These results potentially allow us to design safer medicines, the work on the vitamin D train to help osteoporotic patients," said Jeffrey A. Dodge, PhD, senior research fellow at the Lilly. "These receptor ligand interactions developed technology was critical to understand, in particular at Scripps and a great example of industry academia collaboration is important scientific issues to solve."

Dynamic interactions

In the new study a technology uses the scientists known as the vitamin D receptor complexes measure hydrogen deuterium Exchange mass spectrometry (HDX) the interaction of the different ligands. Ligands can small synthetic compounds, hormones, other proteins or DNA, and they bind to large molecules such as proteins and these molecules change behavior. In this study the ligands have been known vitamin D, a metabolite of vitamin A, DNA and a Coactivator protein as SRC1 (steroid receptor Coactivator 1).

"HDX mass spectrometry is a high-precision, high sensitivity mapping technology", said Griffin. "With him we find the specific regions of the protein complex, which will be affected by the interaction with ligand." "This information can be used to derive structural changes, which are the result of a particular interaction."

In their research, the scientists found that DNA actually complex through a variety of long-range structural effects can change the structure and function of the receptor. It had long-range effects was on the hypothesis, but this study is the first really detection methods directly with high spatial resolution. The changes of these dynamic interactions accomplished were impressive.

The study indicates that events have this binding serious consequences; for example, that the DNA binding to a site changes the stability of both the ligand binding site and Coactivator interaction surface at opposite ends of the complex and vice versa. These changes influence of various important processes of the Coactivator-mediated interactions with various cofactors of the change of the domain binding, so that the specific DNA receptor detects sequences DNA.

"It a complex biochemical dialogue between the receptor, ligand, co-regulation indicates proteins and the specific DNA sequence, the complex nuclear receptor which is bound", Griffin said. "But until this study was not entirely clear what was the structural basis for this crosstalk."

Notes:

The first author of the study, "bind DNA changes Coactivator interaction surfaces of the intact VDR/RXR complex," Zhang Jun's Scripps Research. Other authors include Griffin Yongjun Wang, Scott A. Busby, Bruce D. Pascal, Michael j. Chalmers, Ruben D Garcia Ordonez and Thomas p. Burris from Scripps Research; Keith R. Stayrook, LORRI L. Burris, and Jeffrey A. Dodge of Lilly research laboratories; and John B. Bruning Texas A & M University.

The study was supported by the national institutes of health.

Source:
Mika Ono
Scripps Research Institute