ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis
By P. Towler, B. Staker, S. Prasad, Saurabh Menon, Jin Tang, T. Parsons, D. Ryan, Martin Fisher, David Williams, N. Dales and 2 more. Journal of Biological Chemistry, 2004
602 citations recorded by the source corpus.
The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence. ACE2 has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). To gain further insights into this enzyme, the first crystal structures of the native and inhibitor-bound forms of the ACE2 extracellular domains were solved to 2.2- and 3.0-Å resolution, respectively. Comparison of these structures revealed a large inhibitor-dependent hinge-bending movement of one catalytic subdomain relative to the other (∼16°) that brings important residues into position for catalysis. The potent inhibitor MLN-4760 ((S,S)-2-{1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino}-4-methylpentanoic acid) makes key binding interactions within the active site and offers insights regarding the action of residues involved in catalysis and substrate specificity. A few active site residue substitutions in ACE2 relative to ACE appear to eliminate the S2′ substrate-binding subsite and account for the observed reactivity change from the peptidyl dipeptidase activity of ACE to the carboxypeptidase activity of ACE2.
Subfields: Cardiology and Cardiovascular Medicine, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/192e50f55924aaa00d6d8d3498f29d5a23dbf8db
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Citations in the corpus
- Scalable emulation of protein equilibrium ensembles with generative deep learning (2025, positive): “We show that BioEmu reliably reproduces a stable HEXXH+E motif, the active enzymatic site of this protein [36], with backbone RMSDs below 1.5˚A for all model samples.”
- Severe Acute Respiratory Syndrome Coronavirus as an Agent of Emerging and Reemerging Infection (2007, background): “were also reported to have some activity in vitro (14, 332).”
- Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2 (2005, methodology): “…region of ACE2 remains intact in the presence of an inhibitor that dramati- cally alters the overall conformation of ACE2 (Dales et al, 2002; Towler et al, 2004), consistent with the inability of this inhibitor to block infection, and with the inability of the S protein to modulate ACE2…”
- Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2 (2020, neutral): “SARS-CoV-2 Applies the CTD to Interact with hACE2 Through bioinformatics analysis, the SARS-CoV-2 S protein has been shown to display characteristic CoV S features, including a S1 region containing the NTD andCTD, S2, a transmembrane region, and a short cytoplasmic domain (Figure S1A).”
- Structure, Function, and Evolution of Coronavirus Spike Proteins (2016, background): “The ectodomain of ACE2 contains a membrane-distal peptidase domain and a membrane-proximal collectrin domain (54).”
- The Molecular Biology of Coronaviruses (2006, background): “Recently solved x-ray structures for ACE2 have revealed that a large conformational change is induced by the binding of an inhibitor in the active site of the enzyme (Towler et al., 2004).”