Navigation Links
Molecular 'movies' may accelerate anti-cancer drug discovery
Date:8/17/2012

SALT LAKE CITY Using advanced computer simulations, University of Utah College of Pharmacy researchers have produced moving images of a protein complex that is an important target for anti-cancer drugs. This advancement has significant implications for discovering new therapies that could attack cancer without damaging the DNA of healthy cells, according to an article published July 31, 2012 in the Proceedings of the National Academy of Sciences.

The researchers used high-performance computing technology to demonstrate that a protein complex called LSD1/CoREST undergoes major changes in shape, which are regulated by binding to a DNA-packaging protein known as histone H3. LSD1 gene expression is increased in many cancers and insight into the changes in the LSD1/CoREST complex may help to accelerate development of epigenetic drugs that reprogram cancer cells to behave more normally.

Epigenetics is the study of changes in gene expression that are not caused by alterations in the DNA itself. Instead, these changes are caused by chemical modifications that switch parts of the genome on and off to regulate gene activity. These chemical modifications occur within the epigenome, a layer of chemical labels that covers the genome, and help to determine whether specific genes are active or inactive. Epigenetic drug discovery is based on the knowledge that the epigenome is flexible and could potentially be altered by therapeutic drugs.

Lysine-specific demethylase-1 (LSD1)/CoREST is a protein complex involved in epigenetic changes. Recent studies have shown that LSD1-CoREST is a binding partner for various proteins involved in regulating genes and modifying chromatin, the combination of DNA and DNA-packaging proteins called histones that make up the nucleus of a cell. Previous research also revealed that LSD1-CoREST binds to histone H3.

"In our earlier work, we discovered that LSD1/CoREST functions as a tiny clamp that can reversibly open and close to adjust the size of its binding partners," says Riccardo Baron, Ph.D., assistant professor of medicinal chemistry at the University of Utah and lead author on the study. "The goal of this study was to learn more about the conformational changes that occur when LSD1/CoREST binds to H3."

Baron and Nadeem A. Vellore, Ph.D., postdoctoral researcher in the Baron lab, performed molecular dynamics computer simulation on existing x-ray crystal structures of LSD1/CoREST, effectively transforming a static photo of the protein complex into a molecular movie. They discovered that, in an unbound state, the arms of the LSD1/CoREST clamp exhibit remarkable rotation, shifting back and forth among open or closed configurations. They also found that binding to H3 reduces the overall flexibility of the clamp and triggers a major loss of rotation. These dynamic changes in shape help to explain the ability of LSD1/CoREST to bind to such a wide variety of partners and may also be relevant to how LSD1/CoREST performs chromatin remodeling.

Epigenetics is an active topic in cancer research because an epigenetic mechanism known as DNA or histone methylation is commonly disrupted in cancer cells. In cancer, methylation turns off critical genes, and previous research has suggested that the use of drugs to inhibit the alteration mechanism may lead to re-expression of the affected genes. Unlike traditional chemotherapy drugs, epigenetic drugs would not affect the DNA of healthy cells. This makes epigenetic drug discovery extremely promising for reducing the side effects of chemotherapy.

"Epigenetic drug discovery hinges upon identifying the right protein targets and drug molecules, which is challenging because both are highly dynamic," says Vellore. "It would be extremely difficult to hit a dynamic target using only a static photo. Increasing our understanding of the molecular dynamics of LSD1 has allowed us to screen large compound libraries effectively and to identify the molecules that are most likely to inhibit epigenetic targets."

This research is currently fueling international collaborations with leading experimentalists in enzymology and epigenetics, including the group of Andrea Mattevi at the University of Pavia in Italy.

In the past decades, computing power has steadily risen, increasing by more than one order of magnitude every six years or less. High performance computing using graphic processing units and special-purpose hardware is currently pushing scientific boundaries even further. By taking advantage of such technological advancements, the development and application of chemical theory and computational approaches are becoming increasingly relevant for addressing important biomedical problems.

"My group's long-term goal is to significantly advance the use of computer chemistry in pharmacological applications," says Baron. "I believe in the extremely fascinating idea that physics-based approaches and computers can drive the discovery of new molecules and their practical use."


'/>"/>

Contact: Phil Sahm
phil.sahm@hsc.utah.edu
801-581-2517
University of Utah Health Sciences
Source:Eurekalert

Related biology news :

1. Researchers uncover molecular pathway through which common yeast becomes fungal pathogen
2. Beyond the microscope: Identifying specific cancers using molecular analysis
3. 2012 Forecast for US Molecular Diagnostics Market Now Available From Global Information Inc.
4. 5th Annual Advances in Biomolecular Engineering Symposium
5. PNAS: Precise molecular surgery in the plant genome
6. Molecular spectroscopy tracks living mammalian cells in real time as they differentiate
7. Hitting snooze on the molecular clock: Rabies evolves slower in hibernating bats
8. The activity of a bacterial effector protein seen in molecular detail
9. How bacteria change movement direction in response to oxygen: Molecular interactions unravelled
10. MARC travel award announced for the 2012 GSA Yeast Genetics and Molecular Biology Meeting
11. Highlighting molecular clues to the link between childhood maltreatment and later suicide
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/2/2017)... 2, 2017  EyeLock LLC, a market leader of ... paper " What You Should Know About Biometrics in ... user authenticity is a growing concern. In traditional schemes, ... However, traditional authentication schemes such as username/password suffer from ... authentication offers an elegant solution to the problem of ...
(Date:1/30/2017)... , Jan. 30, 2017   Invitae Corporation ... growing genetic information companies, today announced that it will ... and provide 2017 guidance on Monday, February 13, 2017, ... that day at 4:45 p.m. Eastern / 1:45 p.m. ... team will briefly review financial results, guidance, and recent ...
(Date:1/24/2017)... 2017 Biopharm Reports has carried out ... of nuclear magnetic resonance spectroscopy (NMR). This involved ... current practices, developments, trends and end-user plans over ... and opportunities. These areas include growth in the ... and innovation requirements, hyphenated NMR techniques, main suppliers ...
Breaking Biology News(10 mins):
(Date:2/20/2017)... ... February 20, 2017 , ... ... patients, prevent chest wall collapses in pre-term infants with respiratory distress, and ... total of $600,000 in funding through the ninth round of the University ...
(Date:2/19/2017)... ... February 19, 2017 , ... ... OHAUS Corporation ventured outside of weighing equipment with the goal of expanding the ... in mind, the line of Starter water analysis meters were introduced into the ...
(Date:2/17/2017)... 17, 2017 According to ... Product (Consumables, Service), Type (Safety, Efficacy, Validation), Disease ... Discovery and Development, Disease-Risk) - Global Forecast to ... to reach USD 53.34 Billion by 2021 from ... CAGR of 13.8% during the forecast period (2016-2021). ...
(Date:2/16/2017)... Brussels, Belgium (PRWEB) , ... February 16, 2017 , ... ... Development (SIOTAD) framework primarily aimed at the agricultural industry. Pilot studies are about to ... phytosanitary products through IoT, Big Data and 5G innovations. The concept is expected to ...
Breaking Biology Technology: