How μ-Opioid Receptor Recognizes Fentanyl

Area of Science:

• Structural biology
• Pharmacology
• Computational chemistry

Background:

• Over 70,000 US drug overdose deaths in 2019 were linked to synthetic opioids like fentanyl.
• Fentanyl is a potent agonist of the mu-opioid receptor (mOR), but its binding mechanism remains unclear.
• Previous studies determined mOR structures with morphine derivatives, but not fentanyl-like compounds.

Approach:

• Utilized X-ray structure of mOR with a morphinan ligand.
• Employed weighted ensemble and continuous constant pH molecular dynamics simulations.
• Elucidated the detailed binding mechanism of fentanyl with mOR.

Key Points:

• Fentanyl binds mOR via a salt-bridge with Asp147 and a novel hydrogen bond with His297.
• This secondary binding mode requires His297 to be in a neutral HID tautomer state.
• His297's role in modulating mOR ligand affinity and pH dependence was clarified.

Conclusions:

• The study reveals a unique fentanyl-mOR binding mechanism involving specific histidine tautomerization.
• This finding advances understanding of mOR activation by fentanyl and its analogs.
• The insights may guide the development of safer analgesics to address the opioid crisis.