STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition (Bi3323)

The 4F5W structure represents human STING in its apo (ligand-free) open conformation.

In this state, the STING dimer is open, the C-terminal tail (CTT) remains locked, and the polymerization interface is hidden.

STING is a key immune protein that becomes active when it binds the signaling molecule cGAMP. In its resting form, STING remains open and unable to signal; ligand binding shifts it into a closed, active state, allowing it to recruit downstream partners and trigger interferon production. This balance is crucial because inappropriate activation of STING can lead to severe autoimmune and inflammatory diseases, while insufficient activation weakens antiviral and anticancer immunity.

The apo structure captured in this model represents STING in its natural, inactive condition. It provides the essential reference needed to understand how disease-causing mutations disrupt normal control, how ligand binding drives activation, and how different molecules can either stimulate or inhibit the pathway. This makes the structure valuable not only for understanding STING biology, but also for developing therapeutics that target this pathway in cancer, infection, and autoimmune disorders.

== Function ==STING is a key sensor in our innate immune system. It does not detect DNA directly—instead, when DNA appears in the cytosol, the enzyme cGAS produces a signaling molecule called 2'3'-cGAMP. This cGAMP then binds to STING, triggering its activation.

Once cGAMP binds, several structural changes occur:

The STING dimer closes, shifting from its open resting shape.

The C-terminal tail is released, which is normally tucked away in the inactive state.

This release introduces a polymerization interface, enabling STING molecules to form higher-order structures.

STING then recruits TBK1, leading to the activation of IRF3 and the production of type I interferons, which drive antiviral and anticancer immune responses.

The 4F5W structure captures STING in an open, inactive conformation that is unable to initiate signaling before any of these steps occur.

== Disease == Proper control of STING activity is essential for immune balance. When STING becomes overactive, the body produces too much interferon, which can drive several autoimmune and inflammatory diseases. Examples include:

SAVI (STING-associated vasculopathy with onset in infancy)

Systemic lupus erythematosus

Multiple sclerosis

Aicardi–Goutières syndrome

Certain mutations such as R284S, V147L, and N154S disrupt normal regulation. These mutations can cause the C-terminal tail to come loose even without ligand, pushing STING into a closed, activated-like conformation. As a result, STING forms polymers spontaneously and continuously signals, leading to chronic inflammation.

On the other hand, loss-of-function mutations weaken STING signaling. This results in:

Increased susceptibility to viral infections

A reduced anti-tumor immune response

The apo 4F5W structure represents the healthy, inactive “open” form of STING. It serves as an important reference for understanding how disease-causing mutations shift STING from a normal resting state into an uncontrolled, hyperactive one.

== Relevance == The 4F5W structure is valuable because it captures STING in its true resting, inactive state. This open apo form serves as the baseline against which all ligand-bound and mutated versions of STING are compared.

By having this reference structure, researchers can clearly see how STING changes when different molecules bind:

Apo STING → open and inactive

CDA-bound STING → closed conformation

cGAMP-bound STING → even more tightly closed, fully activated state

These comparisons explain why ligand binding is essential for STING activation and how the structural shift from open to closed directly triggers downstream immune signaling.

Because of this, 4F5W plays an important role in drug development. It helps guide the design of:

STING agonists, which strengthen immune responses for cancer immunotherapy

STING inhibitors, which can calm down excessive signaling in autoimmune and inflammatory diseases

In short, 4F5W provides the structural foundation needed to understand, compare, and therapeutically target the STING pathway.

== Structural highlights == Open dimer conformation (47–54 Å)

In the 4F5W apo structure, the two α2 helices are positioned far apart, creating a wide, open dimer. This open arrangement corresponds to the inactive form of STING and matches the purple structure shown in your image.

Ligand binding drives dimer closure (34–35 Å)

When a ligand such as cyclic-di-AMP binds, the dimer shifts into a much tighter, closed conformation. The gold structure in your image clearly demonstrates this ligand-induced closing movement.

C-terminal tail (CTT) is locked down in the apo state

In 4F5W, the C-terminal tail remains securely tucked into the protein. This prevents:

TBK1 from binding

Any downstream signaling

Any formation of STING polymers

The polymerization interface is hidden

Because the CTT is still in place, the surface needed for polymer formation is not exposed in the apo structure. Only after ligand binding—when the tail is released—does STING reveal this interface and form Cys148-linked polymers.

Apo STING is unable to polymerize

Unlike ligand-bound structures (cGAMP- or CDA-bound STING), the apo 4F5W conformation cannot form linear polymers on the ER membrane. This inability to polymerize explains why the apo form remains fully inactive.

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