Nb80: a VHH that captures GPCR in its active state

Target:
β2-adrenergic receptor (β2AR), an important G protein-coupled receptor (GPCR)

Why it matters:

Nb80 helped solve a long-standing problem in structural biology: capturing a GPCR in its active state.
GPCRs are highly dynamic and rarely “sit still,” making them extremely difficult to visualise when switched on.

What makes it special:

• Conformation-specific binding (recognises the active GPCR state)
• Stabilises a transient protein state long enough for structural determination
• Mimics part of the receptor’s natural signalling machinery (acts like a G protein surrogate)
• Enabled high-resolution structural studies of an activated GPCR
• Demonstrated nanobodies can “lock” dynamic proteins into defined conformations

Big impact:

• Structural biology of GPCRs
• Drug discovery (GPCRs are targets for ~1/3 of approved drugs)
• Understanding receptor activation mechanisms
• Cryo-EM and crystallography of dynamic membrane proteins
• Established nanobodies as tools for stabilising functional protein states

Cool fact:

Nb80 doesn’t just bind the receptor, it effectively mimics the natural G protein interaction, stabilising the active state in a way that allowed researchers to capture one of the first high-resolution “snapshots” of a GPCR switching on.

In other words: it helped turn something too dynamic to photograph into something structurally visible.

References:

Rasmussen SGF, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS, et al. Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature. 2011;469(7329):175–80. doi:10.1038/nature09648.

Steyaert J, Kobilka BK. Nanobody stabilization of G protein-coupled receptor conformational states. Current Opinion in Structural Biology. 2011;21(4):567–72. doi:10.1016/j.sbi.2011.06.011.