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Beauty and the Beast

Structural determinations of life at the molecular level, such as this fibroblast growth factor receptor, can unlock medical mysteries and give drug developers the keys to novel, targeted therapies.
Figure courtesy of John E. Ladbury, Ph.D.

Cylinders of turquoise and purple surrounding chains of electric blue, orange and yellow resemble fireworks against the black computer screen. John E. Ladbury, Ph.D., a professor in The University of Texas MD Anderson Cancer Center's Department of Biochemistry and Molecular Biology and director of the institution's Center for Biomolecular Structure and Function (CBSF), clicks the mouse and swirling ribbons of neon pink and green appear. The color-coded three-dimensional protein structures are eye-popping indeed. As Ladbury explains their relevance in the fields of pharmaceutical and biomedical research, they are nothing short of awe-inspiring. Scientists at the CBSF, one of seven research centers within MD Anderson’s Institute for Basic Science, use X-ray crystallography to turn proteins into these 3-D works of art. They not only are fascinating and beautiful, but also provide fundamental clues to the ways in which proteins function and aid researchers in designing potential new therapies. The process can be arduous and time-consuming.

“We can have a high-resolution atomic structure of a protein in two or three days,” says Ladbury, “or it can take 20 years.”

The process begins with researchers using living cells to produce a given protein of interest. Once the protein has been purified and concentrated, it’s placed in indented trays, each well holding a range of reagents to encourage the proteins to crystallize. The tiny protein crystals are cooled down with liquid nitrogen (“to make them more robust”), then X-rayed from every angle possible. The X-ray beams produce a diffraction pattern on a detector with hundreds of thousands of data points that correlate to the way in which the high energy light source has interacted with atoms in the protein crystal. Finally, the data points are mathematically analyzed to compile structural determinations, detailed molecular snapshots revealing the positioning of atoms with respect to one another in the structure.

John E. Ladbury, Ph.D., and colleagues at the Center for Biomolecular Structure and Function at MD Anderson create pictorial representations of life at its most basic level. Photo by Erin McCormick.

Armed with this pictorial understanding of a protein’s form, scientists and clinicians gain insight into solving complex genetic mysteries and developing new targeted drug therapies aimed at cancer and other diseases.

“Any drug development company not using structural biology is missing an opportunity,” says Ladbury, who recently arrived from London and now holds the Edward Rotan Distinguished Professorship in Cancer Research at MD Anderson.

Studying life at the molecular level in a cell is akin to understanding how the parts of an automobile engine work to repair a component gone awry.

“Knowing the structure of a molecule helps you understand how it works or how it could go wrong, and hence define your target for pharmaceutical intervention,” he says.

A single mutation in the gene that encodes a protein molecule can affect the protein’s function by inducing changes in its three-dimensional shape or by altering its ability to carry out a specific chemical reaction, explains Ladbury. Genetic mutations can cause protein molecules to malfunction, which can lead to cancer and other diseases.

MD Anderson established the CBSF in January 2009 as a collaborative environment for discovery. Ladbury and colleagues Richard G. Brennan, Ph.D., and Maria A. Schumacher, Ph.D., world-renowned experts in structural determination, settled into their laboratories and offices on the seventh floor of the George and Cynthia Mitchell Basic Sciences Research Building and set to work bridging the gap between basic scientists and translational and clinical researchers.

Basic scientists, on the one hand, look at the structures of macromolecules to determine their capacity to carry out normal functions such as gene regulation, DNA replication, DNA repair and cellular signaling — all of which helps translational and clinical researchers as they seek to identify new drug targets (i.e., proteins) and design treatments based on molecular interactions such as binding patterns and signaling pathways. Applying structure-function studies to multidisciplinary research in MD Anderson’s Department of Experimental Therapeutics, Center for Targeted Therapy and Institute for Personalized Cancer Therapy can have a transformational impact on drug discovery and speeding those discoveries to the clinic where they can benefit patients, says Ladbury.

A recent five-year pledge of $500,000 from The Halliburton Foundation helped establish a unique research hub at the CBSF called the Protein Production Group, from which Ladbury predicts a wellspring of new ideas in biomedical research that can be used in preventing and treating all types of disease. Its services are available to members of the Gulf Coast Consortia, which with MD Anderson includes Baylor College of Medicine, Rice University, The University of Houston, The University of Texas Health Science Center at Houston and The University of Texas Medical Branch at Galveston. Ladbury worked with a similar program in London before joining MD Anderson and he has high hopes for the discoveries sure to spin off from the collaboration.

“This is why I came to MD Anderson,” says Ladbury, who was recruited to Houston in 2008 from University College in London. “We have an extremely strong community of structural biologists in the Texas Medical Center and the Gulf Coast area, but there hasn’t been anything to bring these people together. We’re breaking down the barriers between clinicians and structural biologists and making it easier to interface with other disciplines. It’s a fantastic opportunity to bring new and more effective treatments to patients everywhere.” Philanthropic support continues to be crucial in “this whole collaborative effort,” says Ladbury.

“Halliburton’s contribution has been fundamental in setting up the Protein Production Group,” he says. “With the work now in progress, it’s given us a focus and enabled us to build something real that will have a tangible effect on research and new drug development.”

Promise - Summer 2010:


© 2014 The University of Texas MD Anderson Cancer Center