Nav: Home

The pressure's off

January 10, 2019

Bringing a long quest to a satisfying conclusion, researchers have mapped the active-state structure of the angiotensin II type 1 receptor, the target of widely prescribed drugs to regulate blood pressure and kidney function.

The study, published online Jan. 10 in Cell, was conducted by researchers in the Blavatnik Institute at Harvard Medical School and colleagues at Duke University Medical Center.

When the hormone angiotensin attaches to this receptor, it constricts blood vessels to raise blood pressure and stimulates the adrenal glands to retain salt in the kidneys. An estimated 5 percent of adults in the United States take angiotensin II receptor blockers to lower blood pressure, treat heart failure or prevent kidney failure or stroke.

Despite the receptor's critical roles in the body and its popularity as a drug target, researchers have struggled to answer the question: How does it activate?

"Millions of people take drugs that turn this receptor off, and it has been studied very thoroughly, but because of technological limitations, people couldn't see what it looks like when it's turned on," said Andrew Kruse, associate professor of biological chemistry and molecular pharmacology at HMS and co-senior author of the paper with Robert Lefkowitz of Duke.

"Our study provides a framework for interpreting a lot of data that's been collected over the years about the receptor's function, helping to turn disparate pieces into a single coherent model," Kruse said.

The new findings also offer clues about how drugs might be developed that activate, rather than block, the angiotensin II receptor or other receptors in highly controlled ways.

Twist and shout

Like many proteins embedded in the cell membrane, the angiotensin II receptor twists into different shapes depending on whether it's inactive or bound to one protein versus another.

Researchers who want to study a receptor in a specific shape, or conformation, often try to generate an antibody with a complementary shape that will hold the receptor still. Then they can crystallize it, bombard it with X-rays and translate the resulting image into a 3D atomic structure.

Lefkowitz's group tried the standard tactic--inoculating a llama to stimulate its immune system to produce the needed antibodies--but each attempt proved unsuccessful.

"The receptor would flip-flop between all these different conformations," said Lefkowitz. "We tried for at least six years to develop an antibody that would stabilize it, and we failed at every turn."

A tool developed by the Kruse lab in 2018 provided the key. Using yeast instead of llamas, the researchers had generated a library of 500 million artificial nanobodies (small antibodies) to help structural biologists.

One of the nanobodies did exactly what Lefkowitz needed.

"Andrew's new technique, combined with lots of hard, collaborative effort, finally made it possible," he said.

"This is an example of a good collaboration, where we each provided something unique," Kruse agreed. "We offered our nanobody library and expertise in crystallizing G protein-coupled receptors like the angiotensin II receptor, while the Lefkowitz lab brought their strengths in receptor biochemistry and pharmacology."

Conor McMahon, a postdoctoral researcher in the Kruse lab and co-first author of the paper, together with Laura Wingler and Dean Staus in the Lefkowitz lab, added, "This demonstrates the utility of our nanobody library, and it's particularly exciting to see it succeed in a case where llama immunization was unsuccessful."

Details revealed

Capturing the receptor's intricately detailed crystal structure revealed how it binds to angiotensin, how changes on the portion of the receptor outside the cell triggers changes on the portion inside the cell, and more.

"Many of the conformational changes were unique compared to those we'd seen before," said Kruse.

Kruse and team also hope the study will help provide a path to answering questions about the mysterious phenomenon known as biased agonism, in which a protein that binds to a receptor activates one pathway preferentially, rather than activating two or more pathways equally.
-end-
This study was supported by the National Institutes of Health (grants R01HL16037 and 5DP5OD021345), the Mandel Center for Hypertension and Atherosclerosis at Duke University, the Vallee Foundation and the Smith Family Foundation. Lefkowitz is an investigator with the Howard Hughes Medical Institute.

Lefkowitz is a founder and stockholder of Trevena, Inc., and is a director of Lexicon Pharmaceuticals. Kruse is a founder of Ab Initio Biotherapeutics, Inc.

Harvard Medical School

Related Drugs Articles:

Using drugs for different diseases than initially intended for
Thousands of drugs have the potential to be effective against other diseases than they were developed for.
Virtual development of real drugs
systemsDock is a new, free on-line resource that makes screening for drugs faster and more accurate.
Migraine drugs underused
New research shows that more migraines could be safely treated with drugs that are known to constrict blood vessels.
Why cancer drugs can't take the pressure
A major reason why cancer drugs fail is that they cannot penetrate the high-pressure environment of solid tumors.
Designing better drugs
A new strategy for engineering protein fusions -- to make specific cell-targeted drugs without side effects -- could enable a safer, more potent class of protein drugs.
More Drugs News and Drugs Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Teaching For Better Humans
More than test scores or good grades — what do kids need to prepare them for the future? This hour, guest host Manoush Zomorodi and TED speakers explore how to help children grow into better humans, in and out of the classroom. Guests include educators Olympia Della Flora and Liz Kleinrock, psychologist Thomas Curran, and writer Jacqueline Woodson.
Now Playing: Science for the People

#535 Superior
Apologies for the delay getting this week's episode out! A technical glitch slowed us down, but all is once again well. This week, we look at the often troubling intertwining of science and race: its long history, its ability to persist even during periods of disrepute, and the current forms it takes as it resurfaces, leveraging the internet and nationalism to buoy itself. We speak with Angela Saini, independent journalist and author of the new book "Superior: The Return of Race Science", about where race science went and how it's coming back.