The finding, published online April 21, 2013, in the journal Nature by a research collaboration involving this year's Nobel laureates in chemistry, could help in the development of more effective drugs to switch on or off the cell receptors that regulate nearly every bodily function. Already, up to half of all drugs engage these receptors, including antihistamines and beta blockers, but many of the intricacies of how these important proteins work remain unknown.
"It's important to understand how this extraordinary family of receptors work," said co-author Robert J. Lefkowitz, M.D., James B. Duke Professor of Medicine and Howard Hughes Medical Institute Investigator. "This is the kind of finding that answers a basic curiosity, but can also be of benefit if we can develop new drugs or improve the ones we have."
The research marks a collaborative reunion between Lefkowitz and Brian K. Kobilka, M.D., chair of molecular and cellular physiology at Stanford University School of Medicine. The two researchers – friends who first collaborated when Kobilka was a trainee in Lefkowitz's laboratory at Duke - shared the 2012 Nobel Prize in Chemistry for their discoveries involving the G-protein coupled receptors (GPCRs), which are activated by signaling proteins to detect hormones, neurotransmitters, pain, light.
In the current work, the researchers used X-ray crystallography to develop an atom-scale image of one of the principal signaling molecules that regulate GPCRs. This protein is called beta-arrestin1, which, among other things, works to dim a cell's response to hormones such as adrenalin.
The researchers were able to isolate and capture the beta-arrestin1 protein in an active state as it binds to a segment of the GPCR – a first. That snapshot, in high resolution, revealed that the structural conformation or shape of the protein in its active state is strikingly different than when it is inactive.
Such changes suggest there may be a general molecular mechanism that activates the beta-arrestin1 – a sort of main switch that controls the multi-functional signaling proteins.
"It's like there are brakes on in beta-arrestin1, and then when the beta-arrestin1 binds to a GPCR, the brakes are released, thereby activating beta-arrestin1," said Arun K. Shukla, PhD, assistant professor of medicine at Duke and co-lead author of the study.
The researchers are now pursuing additional structural imaging of the signaling complex consisting of beta-arrestin1 and the entire receptor protein.
In addition to Lefkowitz and Shukla, study authors at Duke include Kunhong Xiao, Rosana I. Reis, Wei-Chou Tseng, Dean P. Staus, Li-Yin Huang and Prachi Tripathi-Shukla.
Authors from Stanford include Aashish Manglik, Andrew C. Kruse, Daniel Hilger, William I. Weis and Kobilka. Authors from the University of Chicago include Serdar Uysal, Marcin Paduch, Akiko Koide, Shohei Koide and Anthony A. Kossiakoff.
The study was funded by the Stanford Medical Scientist Training Program, the American Heart Association, the National Science Foundation, the Mathers Foundation and the National Institutes of Health (NS028471, HL16037, HL70631, GM072688, GM087519, HL 075443).
Sarah Avery | EurekAlert!
First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife
Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
26.10.2016 | Physics and Astronomy
26.10.2016 | Earth Sciences
25.10.2016 | Earth Sciences