First Detailed View of Molecular Structure May Usher in New Class of Cancer Drugs

July 26, 2007
First Detailed View of Molecular Structure May Usher in New Class of Cancer Drugs
A side view of the receptor tyrosine kinase Kit in complex with stem cell factor (stem cell factor is colored in magenta). Credit: Yale University

High resolution views of a receptor molecule that is implicated in cancer offer a clear target for the development of a new class of cancer drugs, Yale School of Medicine researchers report July 27 in Cell.

It is also anticipated that the new family of drugs may be applied for the treatment of gastrointestinal stromal tumor (GIST) cancers that are resistant to Gleevec and Sutent. Although these drugs would target the same receptors as Gleevec and Sutent, they would do so by a different mechanism and may therefore be useful for patients who are resistant to these drugs.

“I was surprised to see what the molecules did when they were activated,” said Joseph Schlessinger, professor and chair of pharmacology and senior author of the study. “The arrangement is much simpler and more elegant than I thought.”

The paper, accompanying images, and animation—which looks like a beautiful dance—provide the first detailed, atomic level view of the receptor tyrosine kinase (RTK) Kit before and after it is activated. There are 59 RTK proteins in humans and they play critical roles in the control of a great variety of normal cellular processes as well as in several cancers.

Schlessinger said the newly-revealed mechanism for RTK activation is utilized by many RTKs. “Moreover, these structures offer unexpected new opportunities for drug discovery for the treatment of cancers and other diseases driven by activated RTKs,” he said.

The finding is the result of many years of work involving protein expression, biochemical and biophysical studies and X-ray crystallography, a method used for viewing molecules at a resolution high enough to see atomic detail.

The receptor tyrosine kinase Kit and its natural ligand stem cell factor play an important role in normal blood cell production, gut function, pigmentation, and reproduction. Humans in whom this function is suppressed, or the function is lost, have what is known as a piebald trait—a wing-like discoloration on the chest and abdomen, a white forelock of hair, deafness, and constipation. Mice with the same mutation also have depigmentation and are often anemic and sterile. However, mutations which cause overactivation of Kit are found in a variety of human cancers, among them gastro-intestinal stromal tumors (GIST) and several forms of leukemia.

The structural analysis clearly shows a conformational change as stem cell factor brings two Kit molecules together, resulting in a large rearrangement of and association associations between small parts of the molecules in each pair. Schlessinger said the next step is to identify drugs that can form a wedge in the Kit molecule, making it impossible for them to join together and be activated.

Co-authors include Satoru Yuzawa, Yarden Opatowsky, Zhontang Zhang, Valsan Mandiyan, and Irit Lax.

Source: Yale University

Explore further: All-in-one repair kit makes CRISPR gene editing more precise

Related Stories

All-in-one repair kit makes CRISPR gene editing more precise

November 27, 2017

For the past five years, CRISPR-Cas9 technology has revolutionized the field of gene editing due to its ease and low cost. But although this technology reliably finds and cuts the targeted stretch of DNA sequence, fixing ...

Navigation system of brain cells decoded

October 25, 2017

The human brain contains roughly 100 billion neurons. Information among them is transmitted via a complex network of nerve fibers. Hardwiring of most of this network takes place before birth according to a genetic blueprint, ...

Researchers study the surfaces of ceria nanoparticles

November 16, 2017

At Karlsruhe Institute of Technology (KIT), scientists have studied ceria nanoparticles with the help of probe molecules and a complex ultrahigh vacuum-infrared measurement system and obtained new insights into their surface ...

Watching molecule movements in live cells

July 24, 2013

The newly developed STED-RICS microscopy method records rapid movements of molecules in live samples. By combining raster image correlation spectroscopy (RICS) with STED fluorescence microscopy, researchers of Karlsruhe Institute ...

How cells communicate

January 14, 2015

During embryonal development of vertebrates, signaling molecules inform each cell at which position it is located. In this way, the cell can develop its special structure and function. For the first time now, researchers ...

Recommended for you

Cells lacking nuclei struggle to move in 3-D environments

January 20, 2018

University of North Carolina Lineberger Comprehensive Cancer Center researchers have revealed new details of how the physical properties of the nucleus influence how cells can move around different environments - such as ...

Information engine operates with nearly perfect efficiency

January 19, 2018

Physicists have experimentally demonstrated an information engine—a device that converts information into work—with an efficiency that exceeds the conventional second law of thermodynamics. Instead, the engine's efficiency ...

Team takes a deep look at memristors

January 19, 2018

In the race to build a computer that mimics the massive computational power of the human brain, researchers are increasingly turning to memristors, which can vary their electrical resistance based on the memory of past activity. ...

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.