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 Navigational view of the brain thanks to powerful X-rays
18.10.2017 | Georgia Institute of Technology

nachricht Separating methane and CO2 will become more efficient
18.10.2017 | KU Leuven

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Osaka university researchers make the slipperiest surfaces adhesive

18.10.2017 | Materials Sciences

Space radiation won't stop NASA's human exploration

18.10.2017 | Physics and Astronomy

Los Alamos researchers and supercomputers help interpret the latest LIGO findings

18.10.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>