Researchers define shape of enzyme linked to prostate, breast cancers

January 25, 2012

(Medical Xpress) -- A University of Kansas researcher has made a discovery that should lead to improved treatments for prostate and breast cancer.

Emily Scott, an associate professor of at KU, has provided the first regarding the shape of cytochrome 17A1 – or CYP17A1 – an enzyme that makes hormones that promote the growth of prostate and . By defining the shape of this enzyme, Scott’s research will enable the design of more effective drugs to stop undesirable hormone production in cancer patients.

“To inhibit an enzyme, a needs to bind to it,” Scott said. “But without knowing the shape of an enzyme, designing a drug to bind to it is like designing a key without knowing the shape of the lock. By revealing the shape of CYP17A1, our research will enable the design of better ‘keys,’ or in this case, better drugs.”

Scott’s findings – co-authored by then-graduate student Natasha DeVore – appear this week in the online edition of Nature, the world's most highly cited interdisciplinary science journal. The print edition will be available Feb. 2.

Determining the structure of proteins like CYP17A1 is challenging because they are usually located in cellular membranes and tend to fall apart or stick together when scientists try to study them. Without structural information, previous research used computational studies to predict that drugs designed to inhibit CYP17A1 would orient in a certain way – specifically, parallel to a part of the enzyme called the heme.

But Scott’s research demonstrates that the most promising current treatments bind very differently than previously predicted. Using X-ray crystallography, Scott examined CYP17A1 in the presence of two promising new drugs – abiraterone, which was recently approved by the FDA, and TOK-001, which is in early clinical trials – and found that they bind perpendicularly to the heme, not parallel as previously thought.

“When proteins like CYP17A1 are so difficult to work with, scientists often turn to similar proteins for which more data is available and make a best guess about the protein actually under study,” Scott said. “That is what the previous computational experiments did in this case, and it’s a good start, but there is no substitute for actually doing the experiment – even if the experiment is difficult or time-consuming or expensive. The taxpayer-funded grant investment in this research was well-spent because the current data changes our concepts about how these drugs for and breast cancer are likely to work at the level of atoms.”

In addition to showing how these drugs work, the CYP17A1 structures reveal multiple new opportunities to improve these drugs or design new drugs. Many current drugs, in addition to blocking the enzyme’s cancer-causing activity, also block the enzyme’s normal activities, which leads to side effects in areas like immune response and blood pressure.

“The new data also immediately told us how to design better prostate cancer and breast cancer drugs by making the drugs more complementary to the shape of the enzyme cavity in which they bind,” Scott said.

Scott’s work is funded by the National Institutes of Health via an award to the Center of Biomedical Research Excellence in Protein Structure and Function at KU, and by a grant from the National Institute of General Medical Science. Future work will be funded by a pilot project from the KU Cancer Center. Scott has also submitted a proposal to NIH for additional funding.

Breast cancer is the most frequently diagnosed cancer in women and ranks second as a cause of cancer death in women. Prostate cancer is the most frequently diagnosed cancer and the second-leading cause of death in men.

Explore further: Scientists discover how antibiotic molecule found in bacteria stops breast cancer

Related Stories

Scientists discover how antibiotic molecule found in bacteria stops breast cancer

August 22, 2011
(Medical Xpress) -- Scientists have discovered how a molecule that was first discovered in bacteria blocks a protein which causes breast cancer to develop and spread, reveals research published in Nature Chemistry today.

First evidence of new 'druggable' DNA repair target to destroy cancer cells

November 7, 2011
(Medical Xpress) -- Blocking a key DNA damage repair enzyme, called APE1, could provide a new way to kill cancer cells containing faulty BRCA genes, according to research presented at the National Cancer Research Institute ...

Scientists developing breast cancer treatment test

January 23, 2012
University of Manchester scientists are developing a test that will help identify patients who will benefit from a new breast cancer treatment, thanks to a research grant worth almost £180,000 from Breast Cancer Campaign.

Bacteria shed light on new drug targets for inherited cancers

September 6, 2011
Cancer Research UK scientists have succeeded in purifying a protein found in bacteria that could reveal new drug targets for inherited breast and ovarian cancers - and other cancers linked to DNA repair faults. The study ...

Recommended for you

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

Definitive genomic study reveals alterations driving most medulloblastoma brain tumors

July 19, 2017
The most comprehensive analysis yet of medulloblastoma has identified genomic changes responsible for more than 75 percent of the brain tumors, including two new suspected cancer genes that were found exclusively in the least ...

Novel CRISPR-Cas9 screening enables discovery of new targets to aid cancer immunotherapy

July 19, 2017
A novel screening method developed by a team at Dana-Farber/Boston Children's Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has ...


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.