Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study details structural changes of a key catalytic enzyme

25.09.2006
Findings challenge traditional hypothesis, may aid in drug design

Enzymes are complex proteins capable of catalyzing specific biochemical reactions in cells. While it has long been recognized that dynamic fluctuations in protein conformation or structure play a central role in enzyme catalysis, the new findings indicate that the "dynamic energy landscape" of the enzyme funnels it along a preferred pathway that actually minimizes the number and dimension of the energetic barriers to these catalytic changes.

"There is a growing awareness that the inherent motions of proteins are essential to their functions," said Peter Wright, who is chair of the Scripps Research Department of Molecular Biology and a member of the Skaggs Institute for Chemical Biology at Scripps Research. "The importance of this study is that it reveals how dynamic structural fluctuations channel an enzyme through its reaction cycle-the thermal motions of the protein are harnessed to perform its biological function, in this case, catalysis. Knowledge of the excited-state conformations of proteins may offer new opportunities for drug design."

The researchers used nuclear magnetic resonance (NMR) to detect and characterize higher energy structural sub-states (excited states) of E. coli dihydrofolate reductase, which has been used extensively as a model enzyme for investigating the relations between structure, dynamics, and function in proteins. The researchers found that, at each stage in the catalytic cycle, the excited-state conformations resembled the ground-state structures of both the preceding and the following intermediates. This means that the dynamic fluctuations between the ground state and the excited state were "priming" the enzyme to take up the conformation of the adjacent intermediate state, facilitating the progress of catalysis by aiding the movement of ligands (molecules that bind to one chemical entity to form a larger complex) on and off the enzyme.

"These findings contrast with the traditional 'induced fit' hypothesis," Wright said. "One of the tenets of that hypothesis is that the binding of ligands induces a structural change that increases the complementary relationship between the ligand and the enzyme."

As the study points out, most proteins do not have rigid molecular structures but are structurally heterogeneous; the motion and plasticity in their structure allows them to achieve a far greater range of functions than would be possible with static structures.

However, despite considerable evidence that many enzymes are inherently flexible, the fundamental mechanisms by which protein fluctuations couple with catalytic function remain poorly understood.

In the new conformational model, a small number of minor conformational sub-states that resemble the ligand-bound conformations are already present in solution. When the ligand binds to the minor sub-state, it causes an equilibrium shift so that the ligand-bound conformation becomes the new major sub-state.

"Our study can be placed in the broader context of the catalytic cycle," Wright said. "The results imply that for each of the intermediates in the catalytic cycle of DHFR, the lowest energy excited states are the most functionally relevant conformations. The enzyme structure responds to ligands by taking up a preferred ground-state conformation, but also samples other relevant conformations of higher energy, enabling it to rapidly advance to the next steps in catalysis. As ligands change, the energy landscape and the accessible states of the enzyme change in response. Consequently, this dynamic energy landscape efficiently funnels the enzyme along a specific kinetic path, where the number and heights of the barriers between consecutive conformations have been minimized."

Keith McKeown | EurekAlert!
Further information:
http://www.scripps.edu

Further reports about: Catalysis Dynamic Ligand catalytic enzyme fluctuations sub-state

More articles from Life Sciences:

nachricht Microscope measures muscle weakness
16.11.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

nachricht Good preparation is half the digestion
16.11.2018 | Max-Planck-Institut für Stoffwechselforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: UNH scientists help provide first-ever views of elusive energy explosion

Researchers at the University of New Hampshire have captured a difficult-to-view singular event involving "magnetic reconnection"--the process by which sparse particles and energy around Earth collide producing a quick but mighty explosion--in the Earth's magnetotail, the magnetic environment that trails behind the planet.

Magnetic reconnection has remained a bit of a mystery to scientists. They know it exists and have documented the effects that the energy explosions can...

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Purdue cancer identity technology makes it easier to find a tumor's 'address'

16.11.2018 | Health and Medicine

Good preparation is half the digestion

16.11.2018 | Life Sciences

Microscope measures muscle weakness

16.11.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>