Study offers promising data for improved treatments for cardiac disease

A group of researchers, including Wei Liu, assistant professor in the School of Molecular Sciences (SMS) at Arizona State University and the Center for Applied Structural Discovery at the Biodesign Institute, has recently published an article in the Molecular Cell journal that provides promising data for enhanced therapeutic treatments for cardiac disease.

Assistant Professor Wei Liu of the School of Molecular Sciences and the Biodesign Institute at Arizona State University. Image Credit: Mary Zhu.

Cardiac disease is a leading medical condition that has killed the highest number of people around the world. This disorder kills one individual every 37 seconds in the United States alone, reported the US Centers for Disease Control (CDC).

Keeping this aspect in mind, the researchers decided to perform functional and structural research works by using the cryo electron microscopy (EM) technique to record comprehensive conformational changes that were never seen before. These changes involved the β1-adrenergic receptor, or β1-AR, in complex with the Gs protein.

The β1-AR is a part of the G protein-coupled receptor (GPCR) family—the largest group of membrane proteins found in the human genome.

The β1-ARs are mainly expressed in the heart of adult humans and dominate as a crucial regulator of cardiac function. The stimulated receptor activates the Gs-protein coupling and increases the concentration of cardiac 3′,5′-cyclic adenosine monophosphate, or cAMP.

Such molecular events appear physiologically as increased conduction, increased heart rate, reduced refractoriness inside the atrioventricular node, increased cardiac output, as well as increased contractility.

Most cases of heart failure, which is one of the leading causes of deaths around the world, are caused by the downregulation of β1-ARs.

Beta-blockers—inhibitors of β1-ARs—are used for treating heart failure and high blood pressure to control abnormal heart rhythms, and also to guard against myocardial infarction.

Wei Liu stated, “In this Molecular Cell paper, we employed cryo-electron microscopy and signaling studies to investigate the molecular mechanism by which β1-AR catalyzes the guanine-nucleotide exchange as the result of Gs activation.”

We have captured never-before-seen details of the conformational changes during the Gs activation by isoproterenol-bound β1-AR. Activated β1-AR, serving as a guanine-nucleotide exchange factor (GEF) for Gs, deforms the GDP-binding pocket and induces a tilting of the C-terminal α5-helix and the α-helical domain of Gs rotational opening away from its Ras-like domain.”

Lan Zhu, Study Co-First Author and Assistant Research Scientist, School of Molecular Sciences, Arizona State University

Zhu also works at the Center for Applied Structural Discovery at the Biodesign Institute.

The other first authors of the study are Minfei Su from Cornell University, Yixiao Zhang from The Rockerfeller University, and Navid Paknejad from the Memorial Sloan Kettering Cancer Center.

This structure of the adrenergic receptor complex with the effector G-protein reveals molecular details in the protein-protein interaction domains involved in the receptor activation. This information allows for the design of new precision therapeutics to target cardiac diseases, one of the leading causes of death in the developed world.”

Wei Liu, Assistant Professor, School of Molecular Sciences, Arizona State University

In the last few years, the single-particle cryogenic electron microscopy (cryo-EM) technique has specifically initiated a revolution in the field of structural biology and has turned out to be a new dominant discipline.

The Cryo-EM enables scientists to observe biological structures that were inaccessible just a few years back and is currently revealing structures of unparalleled complexity in excellent detail.

Undeniably, this method is used by specialists in the School of Molecular Sciences and the John M. Cowley Center for High Resolution Electron Microscopy in the College of Liberal Arts and Sciences at Arizona State University that has facilitated the latest study.

Wei Liu’s work is typified by outstanding scholarship and a relentless commitment to making critical advances that will benefit science and society at large.”

Ian Gould, Interim Director, School of Molecular Sciences, Arizona State University

To sum up, these latest outcomes offer structural insights into the activation mechanism of the Gs protein by β1-AR and also provide highly promising details for enhanced therapeutic treatments for cardiac disease.