7kms

Cryo-EM structure of triple ACE2-bound SARS-CoV-2 trimer spike at pH 7.4Cryo-EM structure of triple ACE2-bound SARS-CoV-2 trimer spike at pH 7.4

Structural highlights

7kms is a 6 chain structure with sequence from Homo sapiens and Severe acute respiratory syndrome coronavirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.64Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ACE2_HUMAN Carboxypeptidase which converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator. Also able to hydrolyze apelin-13 and dynorphin-13 with high efficiency. May be an important regulator of heart function. In case of human coronaviruses SARS and HCoV-NL63 infections, serve as functional receptor for the spike glycoprotein of both coronaviruses.^[1] ^[2] ^[3]

Publication Abstract from PubMed

The SARS-CoV-2 spike employs mobile receptor-binding domains (RBDs) to engage the human ACE2 receptor and to facilitate virus entry, which can occur through low-pH-endosomal pathways. To understand how ACE2 binding and low pH affect spike conformation, we determined cryo-electron microscopy structures-at serological and endosomal pH-delineating spike recognition of up to three ACE2 molecules. RBDs freely adopted "up" conformations required for ACE2 interaction, primarily through RBD movement combined with smaller alterations in neighboring domains. In the absence of ACE2, single-RBD-up conformations dominated at pH 5.5, resolving into a solitary all-down conformation at lower pH. Notably, a pH-dependent refolding region (residues 824-858) at the spike-interdomain interface displayed dramatic structural rearrangements and mediated RBD positioning through coordinated movements of the entire trimer apex. These structures provide a foundation for understanding prefusion-spike mechanics governing endosomal entry; we suggest that the low pH all-down conformation potentially facilitates immune evasion from RBD-up binding antibody.

Cryo-EM Structures of SARS-CoV-2 Spike without and with ACE2 Reveal a pH-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains.,Zhou T, Tsybovsky Y, Gorman J, Rapp M, Cerutti G, Chuang GY, Katsamba PS, Sampson JM, Schon A, Bimela J, Boyington JC, Nazzari A, Olia AS, Shi W, Sastry M, Stephens T, Stuckey J, Teng IT, Wang P, Wang S, Zhang B, Friesner RA, Ho DD, Mascola JR, Shapiro L, Kwong PD Cell Host Microbe. 2020 Dec 9;28(6):867-879.e5. doi: 10.1016/j.chom.2020.11.004. , Epub 2020 Nov 17. PMID:33271067^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000 Sep 1;87(5):E1-9. PMID:10969042
↑ Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000 Oct 27;275(43):33238-43. PMID:10924499 doi:http://dx.doi.org/10.1074/jbc.M002615200
↑ Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27;426(6965):450-4. PMID:14647384 doi:http://dx.doi.org/10.1038/nature02145
↑ Zhou T, Tsybovsky Y, Gorman J, Rapp M, Cerutti G, Chuang GY, Katsamba PS, Sampson JM, Schon A, Bimela J, Boyington JC, Nazzari A, Olia AS, Shi W, Sastry M, Stephens T, Stuckey J, Teng IT, Wang P, Wang S, Zhang B, Friesner RA, Ho DD, Mascola JR, Shapiro L, Kwong PD. Cryo-EM Structures of SARS-CoV-2 Spike without and with ACE2 Reveal a pH-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains. Cell Host Microbe. 2020 Dec 9;28(6):867-879.e5. doi: 10.1016/j.chom.2020.11.004. , Epub 2020 Nov 17. PMID:33271067 doi:http://dx.doi.org/10.1016/j.chom.2020.11.004

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OCA

[1] Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000 Sep 1;87(5):E1-9. PMID:10969042

[2] Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000 Oct 27;275(43):33238-43. PMID:10924499 doi:http://dx.doi.org/10.1074/jbc.M002615200

[3] Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27;426(6965):450-4. PMID:14647384 doi:http://dx.doi.org/10.1038/nature02145

[4] Zhou T, Tsybovsky Y, Gorman J, Rapp M, Cerutti G, Chuang GY, Katsamba PS, Sampson JM, Schon A, Bimela J, Boyington JC, Nazzari A, Olia AS, Shi W, Sastry M, Stephens T, Stuckey J, Teng IT, Wang P, Wang S, Zhang B, Friesner RA, Ho DD, Mascola JR, Shapiro L, Kwong PD. Cryo-EM Structures of SARS-CoV-2 Spike without and with ACE2 Reveal a pH-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains. Cell Host Microbe. 2020 Dec 9;28(6):867-879.e5. doi: 10.1016/j.chom.2020.11.004. , Epub 2020 Nov 17. PMID:33271067 doi:http://dx.doi.org/10.1016/j.chom.2020.11.004

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