A high-resolution X-ray structure of the bacterial ribosome, which translates genes into proteins, could help explain how certain antibiotics work and might allow drug designers to develop new types that side-step drug resistance.

Jamie Cate and colleagues at the University of California, Berkeley, and Lawrence Berkeley National Laboratory (LBNL) used the lab's Advanced Light Source to obtain unprecedented structural detail of the bacterial ribosome from Escherichia coli. Many antibiotics, such as the aminoglycosides, only interfere with the entire, fully assembled molecular machine, he explains. "Many antibiotics target only the intact machine, disrupting messenger RNA decoding or movement," says Cate, "We are now in a position to look at some of these drugs and discover things that haven't been known before."

The ribosome of E. coli is about 21 to 25 nm across and relays messenger RNA, decodes it, and expresses the bacteria's proteins. Four years ago, Cate's team published a 5.5 Angstroms structure, their new data are at 3.5 Angstrom. This has allowed the researchers to see the individual nucleotides in the RNA strands of the ribosome and the amino acid backbones of the proteins that surround the RNA core far more clearly.

The researchers obtained two high-resolution snapshots of the intact E. coli ribosome and compared them with a wide range of conformations of other ribosomes. These other data came from lower-resolution X-ray crystallographyic images of Thermus thermophilus and E. coli ribosomes, plus electron microscopy of E. coli, yeast and mammalian ribosomes. Together, they yielded what Cate calls "global snapshots" and allowed him and his colleagues to deduce how individual parts of the ribosome function during the translocation process.

The new structure reveals how the two large pieces of the ribosome bend, ratchet and rotate as the ribosome goes through the repetitive process of protein manufacturing. The precise details are reported in Science and Cate says further exploration is needed to explain the findings. Nevertheless the structure the team obtained should now provide new insights into designing novel antibiotics.
"These are the first high-resolution views of the interface between the two [ribosome]subunits, and also of the various large-scale movements (head of small subunit, L11 arm, i.e.)," Cate told us, "All three of these areas could be useful targets [for antibiotics], i.e. if small molecules could stabilize one state preferentially to the other."

Related links:

• Science, 2005, 310, 827-834
• Cate Page

Article by David Bradley