"These structural studies provide a new level of understanding of the complex structure of ATP receptors, the mechanism of ATP binding and cation channel opening in response to ATP binding. This is an essential window into understanding how ATP receptors function in normal and diseased conditions and ultimately points to a strategy to rational drug design."
- Mary Stenzel-Poore, PhD
Senior Associate Dean for Research
This month's featured paper is from the Eric Gouaux Lab, and is titled, "Molecular mechanism of ATP binding and ion channel activation in P2X receptors." It was published in the journal Nature. The research in this paper was conducted by scientists in the OHSU Department Biochemistry & Molecular Biology, and the Vollum Institute.*
Adenosine-5'-triphosphate (ATP) is well known as a cellular energy source since its discovery in 1929. It has often been called the 'molecular unit of currency' when it comes to intracellular energy transfer. This is because ATP is widely used in energy metabolism, biosynthetic reactions and active transport inside cells.
Studies have shown that ATP is also an extracellular signaling molecule that can be released by exocytosis or by leakage from damaged cells, thereby initiating signaling cascades. Its role in extracellular signaling has attracted great interest in the scientific community since the two distinct classes of extracellular ATP receptors ‑ ionotropic P2X and G-protein-coupled P2Y receptors ‑ were cloned about two decades ago.
P2X receptors, a focus in the Eric Gouaux Lab, are ATP-activated cation channels and are exclusively found in eukaryotes and, most importantly, in humans. To date, seven different receptor subtypes have been identified, named P2X1 through P2X7. These receptors are expressed in a wide variety of cell types in the nervous, cardiovascular and immune systems, and are involved in different physiological functions such as synaptic transmission, contraction of smooth muscle, pain sensation and inflammation.
"P2X receptors are potential drug targets for neuronal, cardiovascular and immune diseases," said Eric Gouaux, PhD, Adjunct Professor, Department of Biochemistry & Molecular Biology and senior scientist at the Vollum Institute. "Although they have attracted significant physiological and pharmacological interest over the years, a high-resolution 3D structure of a P2X receptor was unavailable due to the challenges involved in determining eukaryotic membrane protein structures."
This changed three years ago when scientists in the Gouaux Lab, using the latest technology for the crystallization of membrane proteins, reported the crystal structure of the zebrafish P2X4 receptor in an apo, closed conformation. The first high resolution P2X receptor structure revealed the trimeric architecture of the receptor, which is common in the superfamily of P2X receptors. However, the lack of an ATP-bound structure still hindered the team's understanding of ATP binding and the mechanism of ion channel activation.
In an article recently published in the journal Nature, Dr. Gouaux and Motoyuki Hattori, PhD, reported their latest findings, specifically on the crystal structures of the zebrafish P2X4 receptor in the presence and absence of ATP. In the ATP-bound structure, the investigators found a unique ATP binding motif, which had not been observed in any other known protein structure, and determined the open conformation of the ion channel pore.
"The unique ATP binding motif explains how P2X receptors specifically bind to ATP and not to other nucleotides, ensuring accurate signaling," said Dr. Hattori. "A comparison of the ATP-bound open and ATP-free closed structures suggests how ATP binds to the receptor and triggers channel opening."
"Importantly, this is the first structural insight into how ATP binds and activates the receptor to initiate ATP signaling cascades in response to extracellular ATP," said Dr. Gouaux. "It thus enables other scientists to interpret their studies, completed previously, in the context of the 3D structures."
The new structural information provides investigators with the common mechanism of ATP binding and ion channel activation in P2X receptors, including human orthologs, and thus will accelerate further functional and pharmacological studies which can lead to the development of novel therapeutic reagents targeting P2X receptors.
Pictured above: (top from left) Eric Gouaux, PhD, and Motoyuki Hattori, PhD; (bottom)Ball-and-stick model of adenosine triphosphate (ATP)
Eric Gouaux, PhD and Motoyuki Hattori, PhD
ABOUT THE PAPER OF THE MONTH
The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD.
More Published Papers
The entire list of OHSU papers published this month is here