ACE2 and ACE: structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV

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.

Expression of human ACE2 N-terminal domain, part of the receptor for SARS-CoV-2, in fusion with maltose binding protein,E. coliribonuclease I and human RNase A

“…The protein binding and pull-down results indicate that the SARS-Cov-2 S protein binds poorly to the MBP-ACE2NTD protein, and the RBD protein binds reasonably well to the fusion in vitro. This result is consistent with published data that the SARS-CoV-2 S protein, unlike SARS-CoV-1 S protein, is a poor binder to the human ACE2 receptor in vitro [18; 19; 42]. It remains to be seen whether some recent SARS-CoV-2 variants (e.g.…”

Repurposing of approved drugs with potential to interact with SARS-CoV-2 receptor

“…1 B). Lys353 in the PD of ACE2 is critically important in binding with the SARS-CoV-2 RBD [ 11 ]. Lys363 in the PD of ACE1 is present in a similar position ( Fig.…”

“…The receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of these viruses interact with the extracellular peptidase domain (PD) of ACE2 using electrostatic as well as van der Waals (vdW) forces [ 6 , [8] , [9] , [10] ]. Despite their overall similarities in structures, SARS-CoV-2 spike protein has evolved with a number of sequence variations and conformational deviations from that of SARS-CoV in the RBD that interact with ACE2 [ [6] , [7] , [8] , 11 ]. Structural analyses have revealed the key interactions between the SARS-CoV-2 spike protein RBD and ACE2 [ [6] , [7] , [8] , 11 ].…”

“…Despite their overall similarities in structures, SARS-CoV-2 spike protein has evolved with a number of sequence variations and conformational deviations from that of SARS-CoV in the RBD that interact with ACE2 [ [6] , [7] , [8] , 11 ]. Structural analyses have revealed the key interactions between the SARS-CoV-2 spike protein RBD and ACE2 [ [6] , [7] , [8] , 11 ]. With its modified spike protein SARS-CoV-2 is assumed to bind human ACE2 more efficiently than SARS-CoV [ 7 , 8 , 11 ].…”

“…Structural analyses have revealed the key interactions between the SARS-CoV-2 spike protein RBD and ACE2 [ [6] , [7] , [8] , 11 ]. With its modified spike protein SARS-CoV-2 is assumed to bind human ACE2 more efficiently than SARS-CoV [ 7 , 8 , 11 ]. Binding affinity of the surface spike protein to ACE2 is one of the most important determinants of SARS-CoV-2 infectivity [ 7 ].…”