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Visualizing the unseeable

Ferré-D'Amaré, Stoddard, Strong research reveals structures of molecules that fight tumor cells, metabolize DNA, RNA
TruB is shown in a complex with a transfer RNA molecule
TruB (shaded) is shown in a complex with a transfer RNA molecule (white), a type of RNA involved in protein synthesis. TruB makes a chemical modification on the "elbow" of the L-shaped tranfer RNA. Image courtesy Dr. Adrian Ferré-D'Amaré

Often, the key to how a molecule works is to figure out what it looks like.

That's why structural biologists use a technique known as X-ray crystallography to determine the three-dimensional structures of molecules far too small to be seen with even the most powerful microscope.

In addition to providing clues to function, three-dimensional views of molecules that are possible therapeutic targets often yield insight into drug design.

Drs. Adrian Ferré-D'Amaré, Barry Stoddard and Roland Strong of the Basic Sciences Division published recent studies that reveal the molecular structures of three important biological molecules whose functions range from fighting tumor cells to metabolism of DNA and RNA.

FerFerré-D'Amaré's work

Ferré-D'Amaré and technician Charmaine Hoang determined the structure of a protein called TruB, whose role in the cell is to modify certain types of RNA, a molecule whose structure is similar to DNA. Mutations in the human form of TruB have been shown to cause a disease known as dyskeratosis congenita, which affects the skin and bone marrow.

Although much of the RNA in cells plays the role of messenger in the decoding of DNA into proteins, cells also contain other forms of RNA that play structural roles in the cell.

Most of these structural RNAs contain unusual chemical modifications essential to the RNA's function. TruB carries out the most common modification, a conversion of an RNA component called uridine into pseudouridine.

Ferré-D'Amaré determined the structure of a bacterial form of TruB, although analogous proteins exist in cells of most other organisms. He is the first to demonstrate the structure of an RNA-modifying protein in a complex with the RNA on which it acts.

Ferré-D'Amaré said that a surprising finding of the study was that TruB may be required to help some RNA molecules to fold into their correct shape.

"Proteins in the cell need other proteins, called chaperones, to allow them to fold," he said. "It may be that RNA molecules need chaperones as well, and TruB may play such a role."

Stoddard's work

Stoddard and graduate student Gregory Ireton published the structure of cytosine deaminase, an enzyme found in bacteria and fungi that converts cytosine, one of the building blocks of DNA, into uracil, a component of RNA. Dr. Gerry McDermott of the Lawrence Berkelely National Laboratory and Dr. Margaret Black, a professor at Washington State University, collaborated on the study.

In a separate chemical reaction, cytosine deaminase converts a non-toxic compound called 5-fluorocytosine into 5-fluorouracil, a toxic molecule that also sensitizes cells to radiation. For this reason, cytosine deaminase is of interest as a possible anti-tumor agent. Cytosine deaminase can be introduced into tumor cells by gene therapy, where its production of 5-fluououracil kills cells directly as well as increases the toxic effects of radiation treatment.

Strong's work

Strong, along with his postdoctoral fellow Dr. Pingwei Li and Dr. Gerry McDermott of the Lawrence Berkelely National Laboratory, determined the structure of a complex made up of two mouse proteins whose interaction triggers an immune-system response to kill tumor cells.

Last year, Li and Strong published the three-dimensional structure of the analogous complex in human cells, which consists of the proteins NKG2D and MICA.

Surprisingly, although NKG2D from both mice and humans are largely identical, MICA differs significantly from NKG2D's partner protein in the mouse, known as RAE-1. Typically, protein interactions are highly specific. NKG2D's flexibility is virtually unprecedented in structural biology, Strong said.

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