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
New study points the way to therapy for rare cancer that targets the young
22.11.2017 | Rockefeller University
Penn study identifies new malaria parasites in wild bonobos
21.11.2017 | University of Pennsylvania School of Medicine
Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
23.11.2017 | Information Technology
23.11.2017 | Physics and Astronomy
23.11.2017 | Life Sciences