7JVO

Importin alpha bound to the C-terminus of ACE2

Summary for 7JVO

• Entry DOI: 10.2210/pdb7jvo/pdb
• Descriptor: Importin subunit alpha-1, ARG-LYS-LYS-LYS-ASN-LYS-ALA (3 entities in total)
• Functional Keywords: importin, karyopherin, ace2, transport protein
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 2
• Total formula weight: 56962.40

Authors

Forwood, J.K.,Cross, E.M.,Tsimbalyuk, S. (deposition date: 2020-08-22, release date: 2020-10-14, Last modification date: 2023-10-18)

Primary citation

Tu, W.J.,McCuaig, R.D.,Melino, M.,Rawle, D.J.,Le, T.T.,Yan, K.,Suhrbier, A.,Johnston, R.L.,Koufariotis, L.T.,Waddell, N.,Cross, E.M.,Tsimbalyuk, S.,Bain, A.,Ahern, E.,Collinson, N.,Phipps, S.,Forwood, J.K.,Seddiki, N.,Rao, S.
Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication.
Cell Discov, 7:37-37, 2021

PubMed Abstract: Treatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus-ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus-ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.

PubMed: 34031383
DOI: 10.1038/s41421-021-00279-w

Experimental method

X-RAY DIFFRACTION (2.2 Å)