Key blood-pressure drug seen in startling new detail


April 27, 2015

A new Arizona State University research study has revealed the fine details of how an experimental drug works to regulate blood pressure, paving the way to the development of better drugs.

The ASU team’s interdisciplinary work, led by Petra Fromme of the Biodesign Institute, may one day help scientists better control blood-pressure irregularities with a new class of drugs that could limit harmful side effects. Petra Fromme Download Full Image

The new research focuses on a type of drug known as an angiotensin II receptor blocker, or ARB. Used by millions of people each year, ARBs are designed to block a receptor so it cannot bind with angiotensin II, a hormone that constricts blood vessels to cause an increase in blood pressure.

“Uncovering the structure of the angiotensin receptor is a real breakthrough in the development of better drugs to regulate blood pressure,” Fromme says. It has been unraveled by a new technique called femtosecond crystallography, pioneered by researchers at ASU and their collaborators.

The technique for uncovering these atomic scale structures uses a jet of tiny crystals that are exposed to super-strong X-ray pulses. These powerful bursts of light destroy any solid material but are so short that the structure of the receptor can be discovered before the molecule is destroyed. The structure reveals – in atomic detail – how the drugs block the receptor.

“Many ARBs have been developed, but the interaction between the drug and the receptor has been unknown at the atomic level,” said Vadim Cherezov, a chemistry professor at the University of Southern California (USC) who led the experiment in collaboration with nine other institutions at SLAC’s Linac Coherent Light Source (LCLS) X-ray laser, a DOE Office of Science User Facility.

Solving the structure of the joined ARB and receptor brought researchers a number of surprises. “We have shown that all of the previous molecular models – the best guesses for how receptor and drug fit together – were wrong in many important details,” Cherezov said.

Results of the new study – the first to examine the detailed structure of a drug-receptor complex through high-speed X-ray crystallography – are detailed in the April 23 advanced online edition of Cell.

Under pressure

Given the importance of anti-hypertensive drugs, researchers have sought to uncover agents or mechanisms that will more actively and efficiently control blood pressure, streamline therapy and improve results.

One third of U.S. adults suffer from high blood pressure or hypertension and take prescription medication to treat it. Known as a “silent killer” because the condition often produces no outward symptoms, hypertension is a major risk factor for heart disease and stroke, the leading causes of death in the U.S.

ARBs are a multibillion-dollar industry, with fewer side effects than other hypertension medications. But because their effectiveness at higher doses may be limited, they are often used in combination with other drugs, complicating treatment when patients fail to follow the complete regimen.

In the vast majority of cases, hypertension occurs in primary form, meaning that its underlying causes are unknown. In secondary hypertension, the condition arises as a result of a known affliction, including chronic kidney disease, arterial narrowing or a preexisting endocrine disorder.

Left unchecked, severely elevated blood pressure can lead to a "hypertensive crisis," a condition carrying significant risk of complications. These may include visual deterioration due to retinopathy, breathlessness accompanying heart failure or acute kidney failure. Generally, a hypertensive crisis occurs when some trigger causes already elevated blood pressure to sharply spike.

Crystal clear

The new study examined nanoscale crystals of an experimental ARB coupled to an angiotensin II receptor. The study of such medically important molecules is carried out using brief pulses of intense X-ray light. The tool of choice, a high-speed laser capable of taking vivid snapshots of biological material, uses X-rays a billion times more powerful than conventional light sources.

Like an inkjet printer, a fine spray of tiny crystals of the ARB-receptor pair is injected onto the path of the X-ray beam, which instantly vaporizes the sample.

Crystalized samples are imaged on the scale of femtoseconds. A femtosecond is 0.3 “light micrometers,” a timespan so brief that in 1 femtosecond, a light ray would cross a distance barely the size of a virus. The concentrated X-ray beam vaporizes the sample, but the pulse is so short that the delicate structure is captured before the molecule is destroyed. 

Using femtosecond X-ray crystallography, the researchers were able to precisely determine the crystal structure of angiotensin II type1 receptor at a remarkable resolution, down to 2.9 angstroms (one ten-billionth of a meter – the width of a single hydrogen atom).

Contributions from ASU researchers included the crystallization of samples and biophysical characterization of the drug-receptor constructs, data collection and evaluation, as well as development of the devices that deliver the stream of nanocrystals.

The work is based on a team effort of ASU faculty Petra Fromme, Wei Liu and Uwe Weierstall with their teams of researchers and students, including: Nadia Zatsepin, researcher in the Department of Physics; graduate students Chelsie Conrad and Jesse Coe from the Department of Chemistry and Biochemistry; and Daniel James, Dingjie Wang and Garrett Nelson from the Department of Physics.

In the future, the researchers hope to study the receptor in combination with other drug compounds to fill in even more details and accelerate the design of new drugs to modulate blood pressure and improve human health.

“A further exciting avenue would be to construct a molecular movie of the function of the receptor and the changes induced by the drug binding,” said Fromme. “By obtaining a movie of the dynamics of the receptor and the drug binding, we can eventually design structure-based drugs that block the receptor in action, which might be more efficient and specific, thereby minimizing side effects for the patients.”

In addition to her appointment at the Biodesign Institute, Petra Fromme is a professor in ASU's Department of Chemistry and Biochemistry

Richard Harth

Science writer, Biodesign Institute at ASU

480-727-0378

Liberal arts and sciences faculty honored for quality teaching


April 27, 2015

The College of Liberal Arts and Sciences’ graduating class of 2015 has benefited from the breadth and depth of its professors and lecturers. At the end of the academic year, the college honors and recognizes its faculty for quality teaching.

The Zebulon Pearce Distinguished Teaching Award was established in memory of Zebulon Pearce, who graduated from Territorial Normal School at Tempe (now Arizona State University) with teacher’s credentials in 1899. Professors in the humanities, natural sciences and social sciences departments received this award. Matthew Prior Download Full Image

The college also honored Joanne Rondilla, lecturer at the School of Social Transformation, with the CLAS Outstanding Lecturer Award.

Get to know all of the awardees:

Zebulon Pearce Distinguished Teaching Awards

Matthew Prior, assistant professor

Prior joined the Department of English in 2011 after obtaining his doctorate in second language acquisition at the University of Hawaii. He teaches a variety of graduate courses and serves on several committees and projects in the department. Prior said that his teaching objectives revolve around inspiring and motivating students, engaging with alternative ways of learning and knowing, and cultivating professional development.

“Simply put, I am a teacher because I am first a learner," said Prior. "To see a person transform and grow in knowledge and confidence, and to be a part of that process is rewarding to me, both professionally and personally.”

“[Prior's] commitments to his colleagues and students have already begun to pay large dividends for everyone who comes into contact with this superb mentor, scholar and teacher," said Mark Lussier, chair of the Department of English.

“Dr. Prior stood out to me from any other professors I have had because he makes it clear, from the first day of class, that he is here to assist us students in succeeding not just in his class, but also in the world, as best he can,” shared ASU senior Stephany Caballero.

Steven Semken, associate professor

Semken has worked at ASU since 2007 but he joined the School of Earth and Space Exploration in 2009. He also works as deputy director for education and outreach at the National Science Foundation EarthScope Project National Office. He teaches classes ranging from introductory courses to graduate. For Semken, context plays a huge role in his teaching philosophy.

"I will continue to draw on my education research program to inform and enhance my teaching, and I intend always to teach with unflagging, contagious enthusiasm for my discipline, and with sincere respect for all of my students,” he said.

“He is among our most dedicated faculty who passionately delivers on the fundamental values of place-based education, both in the classroom and nationally. We are very fortunate to have his leadership and high profile,” said Linda Elkins-Tanton, director of the School of Earth and Space Exploration.

“I feel so honored to have had, and continue to have, the opportunity to learn from Dr. Semken. Students remember the professors that touched them the most, through their inspirational teaching as well as their guidance and mentorship, for the rest of their lives. Dr. Semken is one of those very, very few professors for me,” said doctoral candidate Mary Schultz.

Tracy Spinrad, professor

Spinrad began working at ASU in 1997 and joined the T. Denny Sanford School of Social and Family Dynamics in 2000 as an assistant professor. Spinrad said her first-year professor inspired her to pursue an academic path, and she hopes to inspire her students as well. She serves on a number of committees and has helped with more than 20 research publications. Her goal is for students to apply lessons to their own experiences and career goals.

“I believe that students benefit by taking a 'hands-on' approach to their studies, and I strive to create an environment in which students are actively involved in their learning,” she said.

“[Spinrad] is one of the special scholars who is able to integrate her research and teaching, and provide instruction in her classes and in her research projects. She prides herself in taking a strong mentoring role in helping her students understand the research process, in bettering themselves and in facilitating their professional development,” said Richard Fabes, director of the Sanford School.

“I have not known a professor to exert such incredible effort in her commitment to see students thrive in their academic potential. Based on Dr. Spinrad’s outstanding communication skills, her fervor for sharing in her research and knowledge, her initiative for diversity in collaboration and her inspiring mentorship in expanding learning, I have no doubt that she is more than deserving of an award that honors her as a truly exceptional educator,” said ASU graduate Elizabeth Hardin.

CLAS Outstanding Lecturer Award

Joanne Rondilla, lecturer

In 2011, Rondilla joined the Asian Pacific American Studies in the School of Social Transformation. Previously she was an instructor at the University of Berkeley. Since being at ASU, she has helped with the redesign of the curriculum for the Asian Pacific American Studies program. Rondilla said she incorporates relevant material through Youtube or Twitter to show how history still applies to today.

“Teaching is not always about focusing on the particular lesson at hand," said Rondilla. "Instead, it is about connecting that lesson to its larger implications for our students’ lives, and the world at large.”

“Dr. Rondilla has contributed greatly to the ongoing success of ASU students who have taken her courses – even those who have already completed her courses,” said Karen Leong, associate professor of Women and Gender Studies and Asian Pacific American Studies.

“Professor Rondilla is a rare jewel among the ASU faculty, and she outshines them all in every single aspect. What ultimately makes her stand out is her ability to impact and literally change your entire perspective of life for the better. Not every educator can come into a student’s life and revolutionize their education, cultural competency and viewpoints like professor Rondilla did for me and many other students within a single semester,” said ASU sophomore Celina Wang.

Written by Alicia Canales