Abstract
A literature review concerning the unexpected species differences of the vertebrate innate immune response to lipid IVA was published in CSBJ prior to the present computational study to address the unpaired activity-sequence correlation of prototypic E. coli -type lipid A and its precursor lipid IVA regarding human, murine, equine and canine species. To this end, their sequences and structures of hitherto known Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 (MD-2) complexes were aligned and their differential side chain patterns studied. If required due to the lack of the corresponding X-ray crystallographic data, three-dimensional models of TLR4/MD-2/ligand complexes were generated using mono and dimeric crystal structures as templates and in silico docking of the prototypic ligands lipid A, lipid IVA and Eritoran. All differential amino acids were mapped to pinpoint species dependency on an atomic scale, i.e. the possible concert of mechanistically relevant side chains. In its most abstract and general form the three-dimensional (3D-) models devise a triangular interface or “wedge” where molecular interactions between TLR4, MD-2 and ligand itself take place. This study identifies two areas in the wedge related to either agonism or antagonism reflecting why ligands like lipid IVA can possess a species dependent dual activity. Lipid IVA represents an imperfect (underacylated and backbone-flipped), low affinity ligand of mammalian TLR4/MD-2 complexes. Its specific but weak antagonistic activity in the human system is in particular due to the loss of phosphate attraction in the wedge-shaped region conferred by nonhomologous residue changes when compared to crystal and modeled structures of the corresponding murine and equine TLR4/MD-2 complexes. The counter-TLR4/MD-2 unit was also taken into account since agonist-mediated dimerization in a defined m-shaped complex composed of two TLR4/MD-2/agonist subunits triggers intracellular signaling during the innate immune response to bacterial endotoxin exposure.
Highlights
With the advent of crystallography to elucidate membrane protein species-independent strong immunostimulatory activity of lipid A.structures, molecular repositories and software packages, computer Lipid A of the hexa-acylated enterobacerial type represents the central simulations have become widely accepted to gain insight into immunoactivating substructure in lipopolysaccharides biochemical processes on a molecular level, despite certain setbacks (LPS) as characterized for the majority of mammalian commensal [1,2,3,4,5]
To elucidate structural and functional implications regarding the structure-activity analyses of a receptor-ligand array composed of reported species-dependent - either antagonistic or weak agonistic - Toll-like receptor 4 (TLR4) ectdomain/myeloid differentiation factor 2 (MD-2) complexes from four mammalian species activity profile of the tetra-acylated ligand Lipid IVA versus the and three ligands
C.P. 72570 Puebla, Pue., Mexico antagonistic activity changes for the very same ligand are embedded in bDepartment of Hematology and Laboratory for Cellular Therapy, Instituto TLR4/MD-2 sequence differences among mammalian species [8]
Summary
With the advent of crystallography to elucidate membrane protein species-independent strong immunostimulatory activity of lipid A.structures, molecular repositories and software packages, computer Lipid A of the hexa-acylated enterobacerial type represents the central simulations have become widely accepted to gain insight into immunoactivating (endotoxic) substructure in lipopolysaccharides biochemical processes on a molecular level, despite certain setbacks (LPS) as characterized for the majority of mammalian commensal [1,2,3,4,5]. The binding models for liganded TLR4 ectodomain/MD-2 Gram-negative bacteria [6,7]. In comparison to the lipid A and Lipid complexes were generated and sequences and proteins aligned
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