Enabling Proteins with Photocatalytic Functions via HisTag-Iridium Coordination

Area of Science:

• Chemical Biology
• Protein Engineering
• Biochemistry

Background:

• Endowing proteins with new chemical reactivities is crucial for advancing chemical biology and therapeutics.
• Current methods for creating protein-photocatalyst systems often require extensive genetic or synthetic modifications.

Purpose of the Study:

• To develop a minimal and modular strategy for *in situ* formation of iridium-based photocatalysts on proteins.
• To leverage the ubiquitous HisTag for facile installation of photocatalytic activity.
• To demonstrate the versatility of this approach in biological applications.

Main Methods:

• Utilized HisTag-iridium coordination to form iridium-based photocatalysts *in situ* (CAT-tag).
• Employed mild aqueous conditions for the spontaneous conversion of nonphotoactive Ir(III) precursors.
• Tested the CAT-tag system on various protein scaffolds, including nanobodies and therapeutic antibodies.

Main Results:

• Successfully generated luminescent and photocatalytic protein complexes through a single coordination step.
• Demonstrated robust photocatalytic activity across different protein scaffolds.
• Showcased functional versatility including surfaceome labeling, cell-cell interaction mapping, and prodrug activation in living systems.

Conclusions:

• The CAT-tag strategy offers a simple, modular approach to engineer protein photocatalysts without additional genetic modification.
• Repurposing the HisTag transforms a common biochemical handle into a programmable interface for light-driven protein functionalization.
• This method significantly advances protein engineering for chemical biology and therapeutic applications.