Corporate Banner
Satellite Banner
Proteomics
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

Join For Free

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 3,500+ scientific posters on ePosters
  • More than 5,000+ 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

Disordered Protein 'Shape Shifts' to Avoid Crowding
Study suggests disordered protein escapes from the cell membrane when it runs out of space.
Wednesday, September 21, 2016
New Cancer Drug Target Found in Dual-Function Protein
Findings from a study from TSRI have shown that targeting a protein called GlyRS might help to halt cancer growth.
Wednesday, June 29, 2016
HIV Structure Stabilized
Findings represent ‘big accomplishment’ in biomedical engineering and design.
Wednesday, June 29, 2016
Discovering 'Outlier' Enzymes
Researchers at TSRI and Salk Institute have discovered 'Outlier' enzymes that could offer new targets to treat type 2 diabetes and inflammatory disorders.
Saturday, April 02, 2016
Key Morphine Regulator Identified
The findings could lead to less addictive pain medications.
Thursday, September 24, 2015
Novel Role of Mitochondria in Immune Function Identified
Scientists at The Scripps Research Institute (TSRI) have discovered a new role for an enzyme involved in cell death.
Monday, September 21, 2015
Day-Night Cycles Linked to Mutations
TSRI scientists show that proteins critical in day-night cycles also protect cells from mutations.
Friday, March 13, 2015
Possible Neuron Killing Mechanism Behind Alzheimer’s and Parkinson’s Diseases Discovered
$1.4 million grant will enable team to follow up with search for drug candidates.
Tuesday, February 17, 2015
New Targets and Test to Develop Treatments for Memory Disorders
The study focuses on kinesin, a molecular motor protein that plays a role in the transport of other proteins throughout a cell.
Thursday, November 13, 2014
Micah Niphakis Receives ACS Scarborough Award
Niphakis’s research focuses on the development of chemical tools to comprehensively map bioactive molecule-protein interactions in the cell.
Monday, January 21, 2013
Team Discovers Structure of Protein Essential for Quality Control, Nerve Function
Scientists at The Scripps Research Institute have determined the structure of Ltn1, a recently discovered “quality-control” protein that is found in the cells of all plants, fungi and animals.
Monday, January 21, 2013
Scientists Show Protein Linked to Hunger Also Implicated in Alcoholism
Researchers at The Scripps Research Institute have found new links between a protein that controls our urge to eat and brain cells involved in the development of alcoholism.
Monday, September 17, 2012
Scripps Led Team Awarded $22.5 Million for Immune Response Project
The team have received a five-year project renewal from the NIH to uncover the workings of the immune system.
Thursday, August 30, 2012
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
Team Led by Scripps Research Scientists Finds new Way that Cells Fix Damage to DNA
Proteins responsible for this type of DNA repair may also limit the effectiveness of chemotherapy agents, which aim to injure tumor DNA.
Monday, June 15, 2009
Scientific News
Mass Spec Technology Drives Innovation Across the Biopharma Workflow
With greater resolving power, analytical speed, and accuracy, new mass spectrometry technology and techniques are infiltrating the biopharmaceuticals workflow.
One Step Closer to Precision Medicine for Chronic Lung Disease Sufferers
A study led by University of North Carolina at Chapel Hill, and National Jewish Health, has provided evidence of links between SNPs and known COPD blood protein biomarkers.
Designing Drugs with a Whole New Toolbox
Researchers develop methods to design small, targeted proteins with shapes not found in nature.
Protein Studies Discover Molecular Secrets
Two protein studies have mapped proteins that reveal the secrets to recycling carbon and healing cells.
Tapping Evolution to Improve Biotech Products
Researchers show how 'ancestral sequence reconstruction' can be used to guide engineering of a blood clotting protein.
New Weapon Against Hard-to-Treat Bacterial Infections
Using peptides, researchers have been able to prevent drug-resistance bacteria from forming abscesses.
Death-or-Repair Switch Protein Identified
Researchers have identified a protein that plays a key role in the decision process of cell damage repair or cellular suicide.
Gene Regulation in Brain May Explain Repetitive Behaviors in Rett Syndrome Patients
The research could be a key step in developing treatments to eliminate symptoms that drastically impair the quality of life in Rett patients.
CES Score May Predict Response to Cancer Treatment
Researchers identify new type of biomarker that helps predict prognosis and response to several types of cancer treatment.
Gene Deletion Reveals Cell Secrets
Researchers have deleted 174 genes in yeast to analyse the effect of individual gene deletion.
Scroll Up
Scroll Down
Skyscraper Banner

SELECTBIO Market Reports
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
3,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,000+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!