An international team of researchers in cooperation with the University of Bonn has taken two "snapshots" of a receptor which are of critical importance for blood coagulation.
The scientists now hope to be able to develop novel drugs using these results. These include tailor-made blood-thinning substances for heart attack and stroke patients whose effects are reversible and better controllable than those of current therapies. The researchers are presenting their results in the renowned journal "Nature."
After a cut to the finger, blood platelets come into play: they adhere to one another and thus close the wound. The adenosine diphosphate receptor P2Y12, found on the surface of platelets, plays an important role in this essential mechanism. It belongs to the family of so-called G-protein-coupled receptors (GPCR); two American researchers were awarded the Nobel prize in 2012 for research involving these receptors.
"If adenosine diphosphate (ADP) binds to the receptor, signals are transmitted to the inside of the cell which will finally lead to platelet aggregation," said Prof. Dr. Christa Müller from the Pharma-Center of the University of Bonn. In this process, the receptor and its binding partner ADP fit together precisely like a lock and a key. "The ADP can be thought of as a key which unlocks the receptor (the “lock”) to allow the signal for platelet aggregation to pass," explains the pharmacist.
Better control through a reversible blockade
However, platelet aggregation is sometimes undesired. For example, in the case of a heart attack or a stroke aggregated platelets occlude important blood vessels. As a preventive medicine blood thinners are generally prescribed to such patients, in order to prohibit further damage due to occluded blood vessels.
Pills containing the drug clopidogrel, that must be initially activated in the liver, are of great importance, since it blocks the P2Y12 receptor and thus prevents platelet aggregation. Since clopidogrel is an irreversible inhibitor, only with the formation of new platelets after approximately one to two weeks, this effect subsides in the patients.
"An effective, direct, reversible blockade of the receptor would be desirable to be able to better control aggregation and prevent overdose," said Prof. Müller. Also, if a patient treated with clopidogrel meets with an accident, a drug which can quickly detach from the receptor would be advantageous. This would prevent the injured patient from hemorrhaging due to the previously administered blood thinner. Such drugs are being developed, but so far all of them appear to show unwanted side-effects.
Two "snapshots" show the mode of operation of the receptor
"To date, it has not been understood well how exactly the receptor works according to the lock-and-key principle," stated Prof. Müller. "However, this is an important precondition for developing such a reversible, highly effective and, at the same time well tolerated drug with few adverse effects, for the prevention of platelet aggregation."
In an international team under the direction of Chinese colleagues from Shanghai and together with US researchers from Bethesda and La Jolla, the pharmacist was able to take two "snapshots" of the receptor with the help of X-ray structural analysis: once in the "unlocked" state, when a suitable binding partner ensures signal transmission in the platelet. The other shot shows the P2Y12 receptor in the blocked – "locked" – state. This shot has recently been published online in a "Nature" publication.
Both publications will appear in the printed edition of "Nature" in direct succession. "Using these two images, we can now envisage how the receptor protein’s conformation is changed during unlocking," said Prof. Müller. This knowledge will also allow the design of new drugs, which selectively and reversibly block the receptor.
"However, further intensive research is needed until such new drugs will come onto the market," said the pharmacist from the University of Bonn. Since there are many receptors with very similar properties, the research into the P2Y12 receptor gives hope for other applications. Thus the related P2Y2 receptor is, for example, involved in the metastasis of tumor cells. "Here, too, new options for cancer research could arise," said the pharmacist with an optimistic view towards the future.
Agonist-bound structure of the human P2Y12 receptor, journal "Nature", DOI: 10.1038/nature13288
Structure of the human P2Y12 receptor in complex with an antithrombotic drug, journal "Nature", DOI: 10.1038/nature13083
Prof. Dr. Christa E. Müller
of the University of Bonn
Johannes Seiler | idw - Informationsdienst Wissenschaft
Discovery of a novel gene for hereditary colon cancer
29.07.2016 | Rheinische Friedrich-Wilhelms-Universität Bonn
New evidence: How amino acid cysteine combats Huntington's disease
27.07.2016 | Johns Hopkins Medicine
Transparent electronics devices are present in today’s thin film displays, solar cells, and touchscreens. The future will bring flexible versions of such devices. Their production requires printable materials that are transparent and remain highly conductive even when deformed. Researchers at INM – Leibniz Institute for New Materials have combined a new self-assembling nano ink with an imprint process to create flexible conductive grids with a resolution below one micrometer.
To print the grids, an ink of gold nanowires is applied to a substrate. A structured stamp is pressed on the substrate and forces the ink into a pattern. “The...
A new Fraunhofer MEVIS method conveys medical interrelationships quickly and intuitively with innovative visualization technology
On the monitor, a brain spins slowly and can be examined from every angle. Suddenly, some sections start glowing, first on the side and then the entire back of...
Researchers at the U.S. Department of Energy's (DOE) Ames Laboratory have discovered an unusual property of purple bronze that may point to new ways to achieve high temperature superconductivity.
While studying purple bronze, a molybdenum oxide, researchers discovered an unconventional charge density wave on its surface.
Munich Physicists have developed a novel electron microscope that can visualize electromagnetic fields oscillating at frequencies of billions of cycles per second.
Temporally varying electromagnetic fields are the driving force behind the whole of electronics. Their polarities can change at mind-bogglingly fast rates, and...
Breakup of continents with two speed: Continents initially stretch very slowly along the future splitting zone, but then move apart very quickly before the onset of rupture. The final speed can be up to 20 times faster than in the first, slow extension phase.phases
Present-day continents were shaped hundreds of millions of years ago as the supercontinent Pangaea broke apart. Derived from Pangaea’s main fragments Gondwana...
29.07.2016 | Event News
15.07.2016 | Event News
15.07.2016 | Event News
29.07.2016 | Power and Electrical Engineering
29.07.2016 | Life Sciences
29.07.2016 | Event News