Abstract
Angiotensin converting enzyme (ACE) is well-known for its role in blood pressure regulation via the renin–angiotensin aldosterone system (RAAS) but also functions in fertility, immunity, haematopoiesis and diseases such as obesity, fibrosis and Alzheimer’s dementia. Like ACE, the human homologue ACE2 is also involved in blood pressure regulation and cleaves a range of substrates involved in different physiological processes. Importantly, it is the functional receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 responsible for the 2020, coronavirus infectious disease 2019 (COVID-19) pandemic. Understanding the interaction between SARS-CoV-2 and ACE2 is crucial for the design of therapies to combat this disease. This review provides a comparative analysis of methodologies and findings to describe how structural biology techniques like X-ray crystallography and cryo-electron microscopy have enabled remarkable discoveries into the structure–function relationship of ACE and ACE2. This, in turn, has enabled the development of ACE inhibitors for the treatment of cardiovascular disease and candidate therapies for the treatment of COVID-19. However, despite these advances the function of ACE homologues in non-human organisms is not yet fully understood. ACE homologues have been discovered in the tissues, body fluids and venom of species from diverse lineages and are known to have important functions in fertility, envenoming and insect–host defence mechanisms. We, therefore, further highlight the need for structural insight into insect and venom ACE homologues for the potential development of novel anti-venoms and insecticides.
Highlights
Regulatory peptides control various physiological processes ranging from fertilisation and development to immunity and nervous system function
Extensive progress has been made on the structural biology of angiotensin converting enzyme (ACE) over the last two decades
This has been fuelled by the recent COVID-19 pandemic and the urgency to understand the molecular basis for host–viral protein interactions
Summary
Regulatory peptides control various physiological processes ranging from fertilisation and development to immunity and nervous system function. Numerous crystal or cryo-EM structures have been solved of full-length ACE2 or the peptidase domain in complex with the coronavirus spike proteins, small molecule inhibitors or the amino acid transporter B0AT1 [84,85,86,87,88,89,90]. While ACE2 binds a single chloride ion, this is bound in the equivalent Cl1 site of ACE C-domain interacting with ACE2 residues Arg169, Trp477 and Lys481 (Figure 2C) [84].
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