Binding Mechanisms: ACE2 and the SARS-CoV-2 Spike Protein

The ongoing COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has brought intense focus on the molecular interplay between this virus and host cells. In particular, the initial binding event mediated by the SARS-CoV-2 spike glycoprotein and the human enzyme ACE2 represents a crucial step for viral entry and infection. This article provides a comprehensive overview of the spike-ACE2 interface—exploring structural details, binding kinetics, role in pathogenesis, and how this molecular partnership could be exploited for therapeutic interventions against COVID-19.

ACE2: A Key Gateway for SARS-CoV-2 Infection

ACE2, or angiotensin-converting enzyme 2, is a transmembrane metallopeptidase highly expressed in lung alveolar cells, intestinal enterocytes, arterial/venous endothelial cells and other tissues. As part of the renin-angiotensin system regulating blood pressure, it catalyzes the cleavage of angiotensin peptides.

However, ACE2 also moonlights as a critical cellular receptor for coronaviruses. The 2002-2003 SARS-CoV outbreak strain as well as SARS-CoV-2 behind the ongoing COVID-19 pandemic utilize ACE2 to gain entry into host cells.

Spike Protein Mediates Viral Attachment

The trimeric SARS-CoV-2 spike glycoprotein protruding from the viral envelope spearheads binding to ACE2 receptors. It consists of two functional subunits:

• S1 subunit: Contains a receptor-binding domain (RBD) directly interfacing with ACE2.
• S2 subunit: Anchors the protein in the viral membrane and executes membrane fusion post-receptor engagement.

The spike trimer has essentially three “heads” with an RBD each capable of ACE2 attachment in the “up” conformation. Dynamic structural shifts then facilitate subsequent fusion between viral and cellular membranes, allowing viral genetic material to enter host cell cytoplasm and hijack normal biosynthetic pathways.

High-Affinity Binding to ACE2

The incredibly high affinity between the SARS-CoV-2 spike protein and ACE2 receptor underlies efficient viral cell invasion.

Measurements indicate a dissociation constant (Kd) of ~15 nM, about 10-20 times lower than the 2002 SARS-CoV strain. This stronger spike/ACE2 binding for SARS-CoV-2 correlates with generally higher infectivity compared to closely related coronaviruses.

The high-affinity interaction is enabled by a binding interface spanning ~1700 Å2. Central to this is the receptor-binding motif (RBM) on the RBD contacting specific ACE2 residues.

Hotspot Residues at Binding Interface

Several RBD amino acids like Gln493, Asn501 constitute an energetic hotspot, forming multiple hydrogen bonds and van der Waals contacts with ACE2. Corresponding receptor residues Lys31, Gln24, Tyr83, Lys353 complete this intermolecular bridge.

This network of non-covalent bonds across the binding interface provides initial grip for the viral spike protein to latch onto host cells. Researchers are targeting these contact points in designing spike/ACE2 inhibitors.

Structural Dynamics of Spike-ACE2 Engagement

Advanced imaging techniques have provided molecular movies illuminating the step-wise process of SARS-CoV-2 hijacking host cells via the spike-ACE2 nexus.

“Up” Conformation Exposes RBD

First, meta-stable structural rearrangements rotate one RBD into an open “up” state ready for receptor engagement. The two lowered RBDs sterically block the other binding sites.

Initial Attachment to ACE2

The exposed “up” RBD then captures an ACE2 molecule via the hotspot residues described earlier. This initial tethering interaction likely orients the proteins favorably for subsequent tighter binding.

Conformational Change in RBD and Stabilization

Contact with ACE2 triggers movement of the RBD-distal subdomain towards ACE2, closing down on it like a venus fly trap. This sandwiches ACE2, strengthening the interaction.

Structural Rearrangement Exposes Fusion Machinery

Attachment to ACE2 ultimately culminates in release of the spring-loaded S2 fusion machinery buried in the prefusion spike. This extends to fuse viral and host membranes enabling viral genome delivery into the cell cytoplasm.

Role of ACE2 Binding in COVID-19 Severity

The high affinity between SARS-CoV-2 and ACE2 underlying cellular invasion is linked to increased disease severity in several ways:

Widespread Cell Targeting

Binding to ACE2 expressed in lung, arterial, intestinal and other cell types allows the virus to propagate systemically, potentially causing multi-organ failure.

Loss of Protective ACE2 Signaling

Viral engagement with ACE2 also diminishes protective effects of Angiotensin-(1–7) signaling mediated by this enzyme. This exacerbates acute lung injury and cardiovascular complications in severe cases.

Cellular Invasion and Immune Evasion

moreover, spike-ACE2 internalization via endosomes allows membrane fusion and cytoplasmic entry evading initial extracellular immune detection. This sets the stage for exponential viral replication inside cells.

Therapeutic Opportunities Targeting the Spike/ACE2 Interface

Blocking the critical binding step between the SARS-CoV-2 spike and ACE2 offers an attractive avenue for COVID-19 treatment and prophylaxis:

Spike/ACE2 Inhibitors

Designing small-molecule compounds or peptides interfering with spike-ACE2 binding could stop viral attachment and cell entry, preventing infection onset.

Soluble ACE2 Decoys

Administering free recombinant ACE2 proteins would soak up extracellular virus particles like molecular sponges, limiting cells exposed to infection.

Neutralizing Antibodies

Antibodies targeting the SARS-CoV-2 RBD could outcompete or sterically hinder ACE2 attachment to the viral spike protein.

Frequently Asked Questions

How does the SARS-CoV-2 virus bind to human cells?

SARS-CoV-2 utilizes spike glycoproteins projecting from the viral envelope to attach onto ACE2 receptor proteins on the host cell plasma membrane. The receptor-binding domain of the trimeric spike latches onto ACE2 via an extensive network of intermolecular bonds to achieve high-affinity engagement.

What is the role of ACE2 receptors in COVID-19 infection?

As the main cellular gateway for SARS-CoV-2 entry, ACE2 receptor binding sets off a cascade ultimately enabling viral fusion machinery release and injection of genetic material into the cytoplasm. Widespread ACE2 distribution accounts for multi-organ targeting, while its internalization also allows immune evasion.

How does the SARS-CoV-2 spike protein bind the ACE2 receptor?

Dynamic spike rearrangements expose receptor-binding domains to latch onto accessible ACE2 receptors. Specific amino acids like Gln493 and Asn501 constitute hotspots forming hydrogen bonds and vdW contacts with ACE2 residues to initiate gripping. This triggers conformational closure, sandwiching ACE2 to strengthen interaction.

Why is the spike protein-ACE2 affinity higher for SARS-CoV-2 compared to SARS-CoV?

At ~15nM, the measured dissociation constant between the SARS-CoV-2 spike protein and ACE2 is nearly 10-20 times lower than the 2002 SARS-CoV strain. This accounts for generally enhanced infectivity, likely enabled by a larger 1600+ Å2 binding interface with additional intermolecular connections anchoring ACE2.

Can we design COVID-19 treatments targeting the spike-ACE2 binding site?

Yes, the critical spike/ACE2 nexus offers three therapeutic angles – small molecule inhibitors, soluble ACE2 decoys, and neutralizing antibodies interfering with engagement. Blocking this initial step could halt viral attachment/cell entry and infection progression.

Key Takeaways

• The SARS-CoV-2 spike protein binds the host cell receptor ACE2 to gain viral entry.
• High affinity binding underlies efficient infection, with intermolecular hotspots enabling tight engagement.
• Dynamic conformational changes occur, sandwiching ACE2 to trigger fusion machinery release.
• Widespread ACE2 binding causes multi-organ infection and immune escape.
• Targeting the spike/ACE2 interface could yield COVID-19 therapeutics.

I hope this provided comprehensive and engaging coverage explaining the molecular interplay between the SARS-CoV-2 spike protein and the ACE2 cell receptor. Please let me know if you need any sections expanded or have additional questions!

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