Abstract
Opioids are considered the gold standard therapy for pain. However, TLR-dependent negative effects in analgesia have highlighted the complexities in the pharmacodynamics of opioids. While successive studies have reported that morphine and Morphine-3-glucuronide (M3G) activate the TLR4 pathway, the structural details of this mechanism are lacking. Here, we have utilized various computational tools to reveal the structural dynamics of the opioid-bound TLR4/MD2 complex, and have proposed a potential TLR4 activation mechanism. Our results support previous findings, and include the novel insight that the stable binding of morphine and naloxone, but not M3G, in the MD2 cavity, is TLR4 dependent. Morphine interacts with MD2 near its Phe126 loop to induce the active conformation (MD2C); however, this binding is likely reversible, and the complex gains stability upon interaction with TLR4. M3G also induces the MD2C state, with both the Phe126 loop and the H1 loop being involved in MD2-M3G complex stability. Remarkably, naloxone, which requires TLR4 interaction for complex stability, switches the conformation of the gating loop to the inactive state (MD2°). Cumulatively, our findings suggest that ligand binding and receptor clustering occur successively in opioid-induced TLR4 signaling, and that MD2 plasticity and pocket hydrophobicity are crucial for the recognition and accommodation of ligands.
Highlights
Well as a separate in silico docking model, and predicted that morphine, and its opioid-inactive metabolite M3G, bind to the lipopolysaccharide (LPS)-binding pocket of MD2 rather than to TLR414
This study focuses on the structural dynamics of opioid-bound TLR4/MD2, as well as on possible mechanisms for the non-stereoselective activation by morphine and M3G or inhibition of the TLR4 pathway by naloxone
It was recently reported that morphine and M3G are bound within the cavity of MD2, and interact allosterically with other parts of both the dimeric and tetrameric forms of the TLR4/MD2 complex[21]
Summary
Well as a separate in silico docking model, and predicted that morphine, and its opioid-inactive metabolite M3G, bind to the lipopolysaccharide (LPS)-binding pocket of MD2 rather than to TLR414. Successive studies have expanded on these findings to suggest that the activation of the TLR4 pathway by morphine and M3G can be non-stereoselectively blocked by (+/−)-naloxone; this was further supported by in silico model[10]. Both in vivo and biophysical assays have suggested that the binding of morphine to MD2 facilitates the oligomerization of TLR4 and triggers proinflammatory responses. A summary of in silico studies investigating possible morphine, M3G, and naloxone modulation of TLR4, as well as their possible binding interfaces on MD2, is presented in Table 1 5,10,13–16 Structural studies, such as X-ray crystallography and NMR, can reveal the precise orientation of components of protein-protein and protein-ligand complexes. This study focuses on the structural dynamics of opioid-bound TLR4/MD2, as well as on possible mechanisms for the non-stereoselective activation by morphine and M3G or inhibition of the TLR4 pathway by naloxone
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