Recently, researchers at the University of Cape Town (UCT) used cryo-electron microscopy (Cryo-EM) to determine for the first time the full-length structure of human angiotensin-converting enzyme (ACE), a protein that regulates blood pressure and is essential for heart health. This new study of the structure and kinetics of ACE paves the way for improved drug design against hypertension and for the treatment of heart disease. The research paper was published in a recent issue of the EMBO Journal.
ACE is a key target for the treatment of hypertension and cardiovascular disease because it produces angiotensin II, which causes vasoconstriction and elevated blood pressure. Hypertension is a major risk factor for heart failure, heart attack, kidney disease, stroke and blindness. It is often asymptomatic and has been called the “silent killer”. Therefore, there is an urgent need for sustainable solutions for fatal heart disease and other chronic diseases.
The monomeric form of ACE (a copy of the protein) is intriguing because it consists of two structurally similar but functionally distinct structural domains joined together. It also exists as a functionally related dimer (the two interacting copies of the protein observed in the study.) Communication between the different parts of ACE affects its function and drug binding properties, which are critical for therapeutic drug design.
Clinically, ACE inhibitors are recommended as one of the first-line drugs for the treatment of hypertension, but they non-selectively target both monomeric and dimeric regions of ACE, thereby triggering side effects in some patients, the researchers said. The findings of this study uniquely reveal the highly dynamic character of ACE and the mechanisms by which dimerization and exchange occur between its different regions.
The ACE protein was produced in the laboratory. To obtain the complete structure, the researchers rapidly cooled the protein to -180°C and captured the different conformations in a glassy water film in an electron microscopy unit (EMU), followed by high-resolution imaging of ACE using a Titanic Rios microscope.
”Cryoelectron microscopy image processing methods developed in recent years are essential to resolve these structures.” Dr. Lizelle Lubet, first author of the research paper, explains, “We computationally separated the images by extensive classification, which is equivalent to ‘digital purification’ because biochemical methods failed to separate monomers and dimers of ACE. We could then focus on different parts of the structure to resolve the two ACE structures.”
