An important Brandeis study appearing in the December 3 issue of Nature raises the curtain on the hidden lives of proteins at the atomic level. The study reports that for the first time, researchers used x-ray crystallography and nuclear magnetic resonance (NMR) techniques to directly visualize protein structures essential for catalysis at the rare high-energy state. The study also showed how the motions of these rare, or hidden, structures collectively, directly contribute to enzyme catalysis.
In doing so, the study also suggests new molecular sites for potential drug targets, the cornerstone of rational drug design. Drugs may bind, or dock, to the infrequent high-energy states of target enzymes that have been hidden to traditional structural methods. The thinking is that drugs can be designed by docking algorithms to a collection of protein structures, not just one, providing better bio-molecular targeting.
This study comes in the wake of earlier Brandeis studies aimed at advancing understanding of protein function using pioneering techniques such as NMR. For a long time, scientists viewed proteins more or less as macromolecular wallflowers, venturing out onto the atomic-level dance floor to perform only during catalysis, their active state.
Then, several years ago, Brandeis biophysicist Dorothee Kern reported in Nature that her lab's experiments using NMR also linked protein function to their much rarer high-energy state, in the absence of catalysis. That study helped put to rest the conventional wisdom that proteins actually rest at all.
This Nature study takes Kern's research to the next level, seeing the high-resolution structure of the hidden, high-energy state for the first time. For this success, high –resolution x-ray crystallography was further pushed by analyzing electron density data previously discarded as "noise" and by collecting data at ambient temperature. The protein of interest is human cyclophilin A, an enzyme that is highjacked by the HIV virus to aid its own replication.
But it was thanks to some clever protein design together with dynamic NMR spectroscopy that provided direct experimental evidence that the hidden structures in the high-energy state are in fact essential for catalysis. The researchers revealed what happens when proteins flip from the rare state to a major state in a process called interconversion. If this flip is fast, then the enzyme does its job fast, but if the flip is slow, as in the designer enzyme, then the enzyme operates slowly.
"People always focused on the chemistry—accelerating the reaction through catalyzing the chemical step of the substrates. What we've shown is that protein dynamics is as important as the chemical step," said Kern, a Howard Hughes Medical Institute Investigator. "Basically, all the steps need to be choreographed just right, like steps for a beautiful dancer. An enzyme can only function well with the perfect choreography of all the components."
Said Kern: "We now can show directly that the higher energy states are always there and that these hidden, rare states are absolutely essential for protein function."
Laura Gardner | EurekAlert!
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences