Corporate Banner
Satellite Banner
Crystallography
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Scripps Research Institute Study Finds New Moves in Protein's Evolution

Published: Monday, October 07, 2013
Last Updated: Monday, October 07, 2013
Bookmark and Share
Findings point to new approach to drug design.

Highlighting an important but unexplored area of evolution, scientists at The Scripps Research Institute (TSRI) have found evidence that, over hundreds of millions of years, an essential protein has evolved chiefly by changing how it moves, rather than by changing its basic molecular structure. The work has implications not only for the understanding of protein evolution, but also for the design of antibiotics and other drugs that target the protein in question.

“Proteins are machines that have structures and motions,” said TSRI Professor Peter E. Wright, who is the Cecil H. and Ida M. Green Investigator in Biomedical Research and a member of TSRI’s Skaggs Institute for Chemical Biology. “While we’ve known that proteins evolve via structural change, we haven’t really known until now that they also evolve via changes in their dynamics.”

The new study, which appears in Nature Structural and Molecular Biology on September 29, 2013, focuses on the enzyme dihydrofolate reductase (DHFR), which is so important for synthesis of DNA that it is found in almost all living organisms. DHFR is also a frequent target of medicines, including antibiotic, anticancer and antimalarial drugs.

Family Lineage

Wright and his laboratory have been interested in learning more about DHFR so scientists can target it more effectively and better thwart the emergence of drug resistance. In a study published in 2011 in Science, Wright and his colleagues demonstrated that the dynamics of the DHFR enzyme in the common bacterium E. coli are crucial to its catalytic function.

For the new study, the researchers analyzed and compared the dynamics of the E. coli DHFR enzyme with those of human DHFR: despite eons of separate evolution, the human and bacterial enzymes retain very similar atomic-level structures.

The team used a variety of techniques to characterize the two versions of the enzyme, including X-ray crystallography and nuclear magnetic resonance, analyses of DHFR amino-acid sequences and evaluations of the enzyme’s functionality in cells and in vitro under various conditions. They also examined DHFRs from other species in addition to bacteria and humans to get a better idea of the evolutionary paths the enzyme took on its way to higher organisms.

“We didn’t imagine, when we started, how different the dynamics would turn out to be and that there would be an evolutionary pattern of atomic-level dynamics in the enzyme family,” said Gira Bhabha, who was first author of the study. Bhabha, a graduate student at TSRI during the study, is now a postdoctoral researcher at the University of California, San Francisco (UCSF).

E. coli DHFR uses relatively extended motions of flexible amino-acid loops in its active region to grip and release its binding partners. The human enzyme seems to move subtly and efficiently by comparison and essentially with a different mechanism. “The dominant motion in the human enzyme is a clam-shell-like movement with a twist, which allows opening and closing of its active site,” said Bhabha.

Looking Back to Chart a Path Forward

Bhabha and Wright suspect that these strikingly different dynamics of the E. coli and human DHFRs evolved as adaptations to very different cellular environments. Indeed, the human DHFR appears to be so well tuned for working in human cells that—as the researchers found—it cannot work properly in E. coli cells. “It seems that the much higher concentration of product molecules in E. coli cells effectively shuts down the human version of the enzyme,” Bhabha said.

Wright and his laboratory now plan further investigations of DHFR’s dynamics and hope eventually to elucidate the sequence of mutations that occurred to differentiate DHFR in humans and other mammals from the evolutionarily older, bacterial forms of the enzyme.

That evolutionary history should help scientists understand how evolutionary changes in DHFR lead to drug resistance. Knowing how human DHFR differs in its dynamics from its counterparts in bacteria and other disease-causing organisms also should enable researchers to design anti-DHFR drugs that are more specific for the target enzyme and have fewer side effects.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,400+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Scripps Research Institute Scientists Capture Picture of 'MicroRNA' in Action
The Findings Will Help Guide Drug Design.
Thursday, October 30, 2014
Scripps Researchers Find New Point of Attack on HIV for Vaccine Development
The newly identified site can be attacked by human antibodies in a way that neutralizes the infectivity of a wide variety of HIV strains.
Friday, April 25, 2014
Study Reveals How Serotonin Receptors Can Shape Drug Effects from LSD to Migraine Medication
A team of scientists has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor.
Tuesday, March 26, 2013
Scripps Research Institute Scientists Find the Structure of a Key ‘Gene Silencer’ Protein
The structure reveals potential therapeutic targets in area with ‘untapped potential’.
Monday, April 30, 2012
Scripps Research Scientists find E. Coli Enzyme must move to Function
Slight oscillations lasting just milliseconds have a huge impact on an enzyme's function, according to a new study by Scripps Research Institute scientists.
Monday, April 18, 2011
Scripps Research Scientists Solve Protein Structure Revealing Secrets of Cell Membranes
The Findings May Lead to Better Methods to Deliver Drugs
Thursday, May 06, 2010
Scripps Scientists Uncover Mimicry at the Molecular Level that Protects Genome Integrity
Study draws new parallels between the Rad60 DNA repair factor and SUMO; both essential for maintaining genome stability during replication.
Wednesday, April 15, 2009
Scientists Create First Crystal Structure of an Intermediate Particle in Virus Assembly
A research team at the Scripps Research Institute has been able to produce the first crystal structure of a virus particle caught in the midst of assembling its impenetrable outer protein coat.
Monday, March 23, 2009
Scientific News
TOPLESS Plants Provide Clues to Human Molecular Interactions
Scientists at Van Andel Research Institute have revealed an important molecular mechanism in plants that has significant similarities to certain signaling mechanisms in humans, which are closely linked to early embryonic development and to diseases such as cancer.
Advancing Cancer Drug Design with Image of Key Protein
Scientists have pioneered the use of a high-powered imaging technique to picture in exquisite detail one of the central proteins of life – a cellular recycling unit with a role in many diseases.
Mould Unlocks New Route to Biofuels
Scientists at The University of Manchester have made an important discovery that forms the basis for the development of new applications in biofuels and the sustainable manufacturing of chemicals.
'Invisible' Protein Structure Explains the Power of Enzymes
A research group at Umeå University in Sweden has managed to capture and describe a protein structure that, until now, has been impossible to study.
Unraveling the Elusive Structure of HIV Protein
Snapshots of HIV virus’ proteins may help design new ways to fight the disease.
Blueprinting Cell Membrane Proteins
Recent breakthrough will make the blueprinting process faster, easier and cheaper, and should have major implications in the field of drug discovery and development.
Bacteria Use Chemical Harpoons to Hold on Their Hosts
Researchers reveal how a common disease causing bacteria latches on to the body during an infection.
Solving Streptide from Structure to Biosynthesis
Researchers reveal new information about how bacteria communicate via the protein, streptide.
Near-Atomic Resolution of Protein Structure Holds Promise for Drug Discovery
A new study shows that it is possible to use an imaging technique called cryo-electron microscopy to view the architecture of a metabolic enzyme bound to a drug that blocks its activity.
X-ray Study May Aid in Designing Better Blood Pressure Drugs
New atomic-scale details could help create more effective medications with fewer side effects.
SELECTBIO

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,400+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!