9e0i
From Proteopedia
Structure of the HKU5-19s RBD bound to the Bos taurus ACE2 receptor
Structural highlights
FunctionACE2_BOVIN Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis. Converts angiotensin I to angiotensin 1-9, a nine-amino acid peptide with anti-hypertrophic effects in cardiomyocytes, and angiotensin II to angiotensin 1-7, which then acts as a beneficial vasodilator and anti-proliferation agent, counterbalancing the actions of the vasoconstrictor angiotensin II. Also removes the C-terminal residue from three other vasoactive peptides, neurotensin, kinetensin, and des-Arg bradykinin, but is not active on bradykinin. Also cleaves other biological peptides, such as apelins, casomorphins and dynorphin A. Plays an important role in amino acid transport by acting as binding partner of amino acid transporter SLC6A19 in intestine, regulating trafficking, expression on the cell surface, and its catalytic activity.[UniProtKB:Q9BYF1] Publication Abstract from PubMedDPP4 was considered a canonical receptor for merbecoviruses until the recent discovery of African bat-borne MERS-related coronaviruses using ACE2. The extent and diversity of ACE2 utilization among merbecoviruses and their receptor species tropism remain unknown. Here, we reveal that HKU5 enters host cells utilizing Pipistrellus abramus (P.abr) and several non-bat mammalian ACE2s through a binding mode distinct from that of any other known ACE2-using coronaviruses. We defined the molecular determinants of receptor species tropism and identified a single amino acid mutation enabling HKU5 to utilize human ACE2, providing proof of principle for machine-learning-assisted outbreak preparedness. We show that MERS-CoV and HKU5 have markedly distinct antigenicity and identified several HKU5 inhibitors, including two clinical compounds. Our findings profoundly alter our understanding of coronavirus evolution, as several merbecovirus clades independently evolved ACE2 utilization, and pave the way for developing countermeasures against viruses poised for human emergence. Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses.,Park YJ, Liu C, Lee J, Brown JT, Ma CB, Liu P, Gen R, Xiong Q, Zepeda SK, Stewart C, Addetia A, Craig CJ, Tortorici MA, Alshukairi AN, Starr TN, Yan H, Veesler D Cell. 2025 Feb 7:S0092-8674(24)01475-2. doi: 10.1016/j.cell.2024.12.032. PMID:39922192[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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