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The harmonic equilibrium in GPCRs provides important clues about the mechanisms of activation

A multinational research team led by Dr. Adnan Seljoka (RIKEN) and Professor R. Scott Prosser (University of Toronto) in collaboration with Dr. Doi Fuk Tran, Professor Akio Kitao (Tokyo Tech) and Professor Roger K. (University of California, San Diego) conducted experimental and computational studies, which revealed the key steps associated with the activation of the human A2A receptor adenosine (A2AR). A2AR is a member of a super family of receptors called G protein-coupled receptors (GPCRs) (prime drug targets) that turn on the G protein and initiate cell signaling. The research team discovered that A2AR is represented by at least two inactive matches and three active matches whose population depends on the bonds and activation states of protein G, and that the connection between receptor and protein G is important for activation and signaling. It is expected that this study will allow researchers to gain a new level of insight into GPCR activation and disease mechanism.

background

GPCRs affect nearly every aspect of human physiology, with 35% of all drugs approved acting on GPCRs. In most cases, GPCRs are found in the plasma membrane that surrounds the cell while a drug or bond (such as hormones and neurotransmitters) that acts on the GPCR binds to an extracellular pocket. Then the activation is transported via the receptor, which creates a complex with proteins inside the cell. Since the input reaches the outside of the cell and initiates signaling pathways inside the cell, this makes GPCRs useful in pharmacology because in many cases the drug does not need to enter the cell. However, GPCR activations pertain to the main dynamic events and intermediate states that arise between the time when the ligand is bound and when the G protein is activated. Capturing the conformational dynamics of GPCRs and describing the intermediate states and their role in activation and signaling was a formidable challenge, which impeded progress in understanding the mechanisms. Activate GPCRs.

Research completion overview

Using nuclear fluorin magnetic resonance (19F-NMR), mathematical stiffness theory, and simulation of molecular dynamics, the international research team discovered the key mechanism for activating the human A2A receptor (A2AR) as it advances through the signaling pathway. A2AR (also known as caffeine receptor antagonist because it is inactivated by caffeine) is a well-known GPCR that is distributed in the nervous system, platelets, immune cells, lungs, heart, and blood vessels. A2AR drugs were developed to treat wound healing and vascular disease, including atherosclerosis, restenosis, and stimulation of platelets, as well as inflammation and cancer. Thus, an understanding of the functional states associated with receptor signaling could lead to new opportunities in pharmacology and a general understanding of the mechanisms of GPCR activation. The researchers focused on the bias of the key A2AR conformational states through their complexity with different G protein and ligands to better understand signal transduction and receptor activation. F-NMR showed that A2AR is represented by at least two inactive matches and three active matches linked to the signaling pathway whose population depends on the binding and G protein interactions (Fig.2). The research team also used molecular dynamics simulations to create a structure of A2AR bound to the heterozygous G-protein complex (conducted by Kitao’s lab), where Sljoka’s stiffness theory methods identified an activation pathway where A2AR initiates contact with the G-protein that crosses the receptor. The ligand and protein G binding site (Figure 3). The Gβγ unit was discovered to serve as a critical domain to facilitate signaling and activation. Understanding the activation mechanism and functional states of A2AR signaling may provide new opportunities for drug discovery.

Future developments

While the current study provides unprecedented resolution for the major functional states associated with receptor signals, future studies will undoubtedly focus on other key areas, providing a more comprehensive picture of the activation process.

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About Tokyo Institute of Technology

Tokyo Tech is at the forefront of research and higher education as the leading university in science and technology in Japan. Tokyo Tech researchers excel in fields ranging from materials science to biology, computer science and physics. Founded in 1881, Tokyo Tech hosts over 10,000 undergraduate and graduate students annually, who develop into scientific leaders and some of the most sought-after engineers in the industry. Embodying the Japanese philosophy of “monotsukuri,” which means “technical creativity and innovation,” the Tokyo Tech community strives to contribute to society through high-impact research.
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