Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New and sharper X-rays of cell’s ribosome could lead to better antibiotics

04.11.2005


A new, sharper picture of the nano-machine that translates our genetic program into proteins promises to help researchers explain how some types of antibiotics work and could lead to the design of better ones.



The high-resolution snapshots of the bacterial ribosome were captured by scientists at the University of California, Berkeley, and Lawrence Berkeley National Laboratory (LBNL) with the lab’s Advanced Light Source, which generates intense beams of X-rays that can reveal unprecedented structural detail of such large and complex molecules.

The new, high-resolution data on the intact ribosome allows researchers to build more detailed and more realistic models of the ribosome that until now were impossible with the "fuzzy pictures" available.


While sharp images of the two main pieces of the ribosome have already provided great insight into how specific antibiotics work, many antibiotics, such as the aminoglycosides, only interfere with the entire, fully assembled molecular machine.

"Many antibiotics target only the intact machine, disrupting messenger RNA decoding or movement," said lead author Jamie Cate, assistant professor of chemistry and of molecular and cell biology at UC Berkeley and a staff scientist in the Physical Biosciences Division at LBNL. "We are now in a position to look at some of these drugs and discover things that haven’t been known before."

Cate, a member of the California Institute for Quantitative Biomedical Research (QB3) at UC Berkeley, and his colleagues report the detailed structure of the ribosome from Escherichia coli, the common intestinal bacteria, in the Nov. 4 issue of Science.

The ribosome, about 21 to 25 nanometers across, is the original nanomachine, taking genetic information relayed by messenger RNA, decoding it and spitting out proteins. Ribosomes are dispersed in the hundreds of thousands throughout the cell, and in some highly active cells, ribosomes are responsible for producing millions of proteins per minute.

Ribosomes are found in all organisms, ranging from bacteria to humans, and probably arose nearly 2 billion years ago. They have changed so little through evolution that a bacterial ribosome can often translate human genes into protein. Some people suspect that ribosomes, which at their core consist of ribonucleic acid (RNA), a sister of the DNA that comprises our genes, arose when RNA, not DNA, carried our genetic dowry.

Because of its importance to life, and the fact that important drugs target the ribosome, it has received lots of attention. Only four years ago, Cate was part of a team that published a picture of the ribosome with a resolution of 5.5 Angstroms, where an Angstrom, about the size of a hydrogen atom, is one-tenth of a nanometer. The new images have a resolution of 3.5 Angstroms, allowing Cate and his colleagues 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.

Both the old and new images were obtained through X-ray crystallography using Advanced Light Source beamlines, which provide extremely bright X-ray sources. Having the light source in his backyard, Cate said, has made it easier to get the best crystallographic picture with the sharpest three-dimensional detail. He and his laboratory colleagues grow crystals of ribosomes, check their quality in the light source, then tweak the crystals and try again.

"We’ve burned through thousands of crystals in the last five years," he said.

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.

What the new structure shows so far is how the two large pieces of the ribosome bend, ratchet and rotate as the ribosome goes through the repetitive process of protein manufacturing.

The "small" subunit of the ribosome first recognizes and latches onto the messenger RNA (mRNA), which contains a copy of part of the chromosomal DNA. Once the small subunit finds the start position, the "large" subunit moves in and latches on, clamping the mRNA between them. The combined machine slides along the mRNA, reading each three-letter codon, matching this code to the appropriate amino acid, and then adding that amino acid - one of 20 possible building blocks - to the lengthening protein chain.

As this translation takes place, transfer RNA (tRNA) constantly brings in amino acid building blocks, while energy-supplying molecules in the form of GTP (guanosine triphosphate) cycle through.

They found that after the bond - called a peptide bond - forms between the growing chain and the newly added amino acid, the small subunit ratchets with respect to the large subunit. Then the head of the small subunit swivels in preparation for shifting the mRNA forward by one codon. At the same time, a groove opens that allows the mRNA to actually move and the tRNA, depleted of its amino acid, to float away.

Then, the small subunit reverses its motions, resets, and is ready to add the next amino acid. This picture of translocation - ratcheting, swiveling, opening the groove, then reversing these three steps - is repeated 10 to 20 times each second in bacteria.

Based on the researchers’ analysis of the new data, Cate said that it appears, also, that the helical RNA in the ribosome acts as a spring to withstand the stress of these reversible swivels. Also, the ribosome harbors an astounding number of positive magnesium ions - hundreds in all - that apparently neutralize the highly negative charge of the RNA. Without these magnesium ions, Cate said, the repulsion of the RNA’s negative charge would blow the ribosome apart. Some of the magnesium ions form a salty liquid at the interface between the large and small subunits of the ribosome, perhaps lubricating the machine.

These and other hypotheses need further exploration, he said.

"All the interactions we see have been seen before at lower resolution, but it was not clear how to interpret them," he said. "It took these high-resolution studies to coalesce our ideas."

Robert Sanders | EurekAlert!
Further information:
http://www.berkeley.edu

More articles from Life Sciences:

nachricht Switch-in-a-cell electrifies life
18.12.2018 | Rice University

nachricht Plant biologists identify mechanism behind transition from insect to wind pollination
18.12.2018 | University of Toronto

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Data storage using individual molecules

Researchers from the University of Basel have reported a new method that allows the physical state of just a few atoms or molecules within a network to be controlled. It is based on the spontaneous self-organization of molecules into extensive networks with pores about one nanometer in size. In the journal ‘small’, the physicists reported on their investigations, which could be of particular importance for the development of new storage devices.

Around the world, researchers are attempting to shrink data storage devices to achieve as large a storage capacity in as small a space as possible. In almost...

Im Focus: Data use draining your battery? Tiny device to speed up memory while also saving power

The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.

Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Pressure tuned magnetism paves the way for novel electronic devices

18.12.2018 | Materials Sciences

New type of low-energy nanolaser that shines in all directions

18.12.2018 | Physics and Astronomy

NASA research reveals Saturn is losing its rings at 'worst-case-scenario' rate

18.12.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>