Structure of dimeric full-length human ACE2 in complex with B⁰AT1

Abstract

Angiotensin-converting enzyme 2 (ACE2) is the surface receptor for SARS coronavirus (SARS-CoV), directly interacting with the spike glycoprotein (S protein). ACE2 is also suggested to be the receptor for the new coronavirus (2019-nCoV), which is causing a serious epidemic in China manifested with severe respiratory syndrome. B 0 AT1 (SLC6A19) is a neutral amino acid transporter whose surface expression in intestinal cells requires ACE2. Here we present the 2.9 Å resolution cryo-EM structure of full-length human ACE2 in complex with B 0 AT1. The complex, assembled as a dimer of ACE2-B 0 AT1 heterodimers, exhibits open and closed conformations due to the shifts of the peptidase domains (PDs) of ACE2. A newly resolved Collectrin-like domain (CLD) on ACE2 mediates homodimerization. Structural modelling suggests that the ACE2-B 0 AT1 complex can bind two S proteins simultaneously, providing important clues to the molecular basis for coronavirus recognition and infection.

COVID-19: what has been learned and to be learned about the novel coronavirus disease

“…The orf3b of SARS-CoV-2 may play a role in the viral pathogenicity and inhibit the expression of IFNβ; however, orf8 does not contain any known functional domain or motif [20]. On February 18, 2020, Zhou, et al, reported the cryo-EM structure of the full-length human ACE2 at 2.9 Å resolution in complex with the amino acid transporter B 0 AT1 [21]. They found that the complex, which had open and closed conformations, was assembled as a dimer and the ACE2-B 0 AT1 complex can bind two S proteins, which provides evidence for CoV recognition and infection.…”

ACE2 polymorphisms and individual susceptibility to SARS-CoV-2 infection: insights from anin silicostudy

“…There is evidence that ACE2 may serve as a chaperone for membrane trafficking of an amino acid transporter B0AT1 (also known as SLC6A19), which mediates the uptake of neutral amino acids into intestinal cells in a sodium dependent manner 19 . Recently, 2.9 Å resolution cryo-EM structure of full-length human ACE2 in complex with B0AT1 was presented, and structural modelling suggests that the ACE2-B0AT1 can bind two spike glycoproteins simultaneously 20,21 . It has been hypothesized that the presence of B0AT1 may block the access of TMPRSS2 to the cutting site on ACE2 20,21 .…”

“…Recently, 2.9 Å resolution cryo-EM structure of full-length human ACE2 in complex with B0AT1 was presented, and structural modelling suggests that the ACE2-B0AT1 can bind two spike glycoproteins simultaneously 20,21 . It has been hypothesized that the presence of B0AT1 may block the access of TMPRSS2 to the cutting site on ACE2 20,21 . B0AT1 (also known as SLC6A19) is expressed with high variability in normal human lung tissues, as shown by analysis of data available in Oncomine from the work by Weiss et al 22 .…”

COVID-19 and Liver Dysfunction: Current Insights and Emergent Therapeutic Strategies

“…Full-length ACE2 consists of an N-terminal peptidase domain and a C-terminal collectrin-like domain that ends with a single trans-membrane helix and a ;40-residue intracellular segment. 38 Glycyrrhizin has the potential to bind to ACE2 receptor with an estimated DG (kcal/mol) of -9, with the binding sites of ARG-559, GLN-388, ARG-393, and ASP-30. 36…”