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Environmental Factor, December 2015

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Distinguished lecturer advances nuclear receptor field

By Shannon Whirledge

Bert O'Malley, Ph.D.

O’Malley completed his training at the University of Pittsburgh and the National Cancer Institute, before heading his own research group at Baylor College of Medicine in Houston, Texas. He was awarded a National Medal of Science in 2007. (Photo courtesy of Steve McCaw)

Ken Korach

Acknowledging O’Malley’s many accomplishments, Korach joked during his introduction that he had never seen a 98-page curriculum vitae. (Photo courtesy of Steve McCaw)

As key regulators of hormone action, nuclear receptors are targeted in the treatment of many human diseases. Bert O’Malley, M.D., is a pioneer of nuclear receptor biology, having devoted more than 50 years to the field. He discussed current advances in the understanding of nuclear receptors during a Nov. 10 NIEHS Distinguished Lecture Seminar Series talk titled, “Deciphering the Structure of a Biologically Active Nuclear Receptor-Coactivator Complex on DNA.”

Coactivators hold the key

O’Malley began his seminar by explaining that the key to gene expression comes from the recruitment of coactivators to DNA. Coactivators enhance gene expression by binding to proteins known as transcription factors. O’Malley discovered the first steroid receptor coactivator (SRC-1) in 1995 and has since revolutionized the understanding of how gene expression is regulated.

He is currently using new techniques to visualize the recruitment of receptors and coactivators, and the conformational changes, or changes in the structure or shape of a molecule, that occur as gene transcription begins. O’Malley believes that understanding how this process occurs will lead to novel, targeted therapies for cancer. Fellow nuclear receptor researcher Kenneth Korach, Ph.D., chief of the Reproductive and Developmental Biology Laboratory, hosted O'Malley's talk.

Novel approaches to answer long-standing questions

Nuclear receptors play a major role in determining cell fate by regulating development, differentiation, and maintenance of cells. Scientists have long sought to determine how nuclear receptors bind to coactivators at sites of transcription.

Baylor College of Medicine, where O’Malley is chair of molecular and cellular biology, has one of the select few labs that use cryo-electron microscopy (Cryo-EM), via the lab of Wah Chiu, Ph.D. Resolving the structure of protein complexes by Cryo-EM, which images frozen samples, is an additive approach. O’Malley and his group have been able to image each protein alone and then reconstruct each shape as a piece of the protein complex puzzle. He claimed it was entirely a coincidence that the structure of SRC-3 resembles Texas, the state in which it was discovered.

New insights from unique visualizations

In an approach not possible using conventional techniques, researchers were able to visualize new regions of the estrogen receptor, by further refining the data using antibodies that target specific regions of the protein. With this approach, O’Malley determined that the receptor complex functions as a flexible platform in which coactivator proteins may be exchangeable.

He said that the same approach can be used to determine how protein complex formation changes in the presence of endocrine disruptors, which often have their own unique gene expression signature.

Mentoring advice from a giant in the field

Following his seminar, O’Malley sat down with NIEHS trainees to discuss their projects and offer advice. He stressed the need to be adaptable in science by illustrating that at the beginning of his career in reproductive biology, the focus in the field was on contraception, but now it is on infertility. “It’s the same question, just flip the switch,” he said. In addition to being adaptable, O’Malley said researchers need to be aware, investigative, and industrious in finding funding.

O’Malley shared a frank perspective on beginning a tenure-track career. “The good news is you are on your own. The bad news is you are on your own,” he said. However, he pointed out that the risk is worth the reward. “Biological research is the best job in the world. There are not many jobs where you don’t mind coming home late, working at home, or just thinking about work while away from the job,” he said. That passion for research has driven his long and distinguished career.

(Shannon Whirledge, Ph.D., is a Research Fellow in the NIEHS Laboratory of Signal Transduction.)

Darryl Zeldin, Ph.D. and Trevor Archer, Ph.D.

Darryl Zeldin, M.D., right, NIEHS scientific director, looked on as Trevor Archer, Ph.D., left, head of the NIEHS Epigenetics and Stem Cell Biology Laboratory, asked O’Malley about the applications of his discoveries. (Photo courtesy of Steve McCaw)

Donald McDonnell, Ph.D.

Donald McDonnell, Ph.D., left, chairman of the Duke University Department of Pharmacology and Cancer Biology, also studies nuclear receptor signaling and did not miss the opportunity to hear O’Malley’s talk. He is seated next to John Cidlowski, Ph.D., head of the NIEHS Signal Transduction Laboratory and lead researcher for the Molecular Endocrinology Group. (Photo courtesy of Steve McCaw)

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