Full‐Atom Model of the Agonist LPS‐Bound Toll‐like Receptor 4 Dimer in a Membrane Environment

Abstract

The Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) innate immunity system is a membrane receptor of paramount importance as therapeutic target. Its assembly, upon binding of Gram-negative bacteria lipopolysaccharide (LPS), and also dependent on the membrane composition, finally triggers the immune response cascade. We have combined ab-initio calculations, molecular docking, all-atom molecular dynamics simulations, and thermodynamics calculations to provide the most realistic and complete 3D models of the active full TLR4 complex embedded into a realistic membrane to date. Our studies give functional and structural insights into the transmembrane domain behavior in different membrane environments, the ectodomain bouncing movement, and the dimerization patterns of the intracellular Toll/Interleukin-1 receptor domain. Our work provides TLR4 models as reasonable 3D structures for the (TLR4/MD-2/ LPS) 2 architecture accounting for the active (agonist) state of the TLR4, and pointing to a signal transduction mechanism across cell membrane. These observations unveil relevant molecular aspects involved in the TLR4 innate immune pathways and will promote the discovery of new TLR4 modulators.

Peptidoglycan recognition protein S2 is crucial for activation the Toll pathway against Israeli acute paralysis virus infection in honey bee Apis mellifera

“…Our co-immunoprecipitate assay between PGRP-S2 and Toll displayed an enhanced PGRP-S2-mediated activation of the Toll pathway in a PGRP-S2 dependent manner. Generally, pathogens promoted the dimerization of the Toll/Toll-like receptor, bringing together the corresponding cytoplasmic Toll/interleukin-1 receptor (TIR) domains which also dimerize [34]; our result also showed the IAPV infection accelerated the Toll to dimerize ( Fig 6 ). As shown in Fig 6 , PGRP-S2 was significantly localized in cell surface with Toll and indicated that PGRP-S2 could be a membrane protein.…”

Small Molecules as Toll-like Receptor 4 Modulators Drug and In-House Computational Repurposing

“…TLR4 is specialized in the recognition of lipopolysaccharides from Gram-negative bacteria through the extracellular domain (ectodomain) with the participation of an essential coreceptor, myeloid differentiation factor 2 (MD-2) ( Figure 1 ) [ 66 , 79 , 80 , 81 ]. The LPS fatty acid chains are inserted into the MD-2 pocket while the oligosaccharide binds to TLR4 and the partner TLR4.…”

“…The LPS fatty acid chains are inserted into the MD-2 pocket while the oligosaccharide binds to TLR4 and the partner TLR4. Dimerization of the ectodomain promotes the TLR4/MD-2 dimerization at the intracellular site and recruitment of the binding of adaptor proteins that finally triggers the activation of downstream signaling and the inflammatory response ( Figure 1 ) [ 79 , 80 , 81 ].…”

“… ( A ) Full-atom 3D model of the agonist LPS-bound TLR4 dimer in a membrane environment [ 81 ]; ectodomain is framed in a red box. ( B ) X-ray structure of the TLR4/MD-2 dimer in complex with E. coli LPSs (from PDB ID 3FXI).…”

Multifaceted Computational Modeling in Glycoscience

“…A series of molecular modeling and computational studies have provided insights into the mechanism regulating the activation/inactivation of the TLR4/MD-2 system receptor and the fundamental interactions modulating the molecular recognition process by agonist and antagonist ligands (Figure ). − …”