title: The Structural Basis for Lipid and Endotoxin Binding in RP105-MD-1, and Consequences for Regulation of Host Lipopolysaccharide Sensitivity.
abstract: MD-1 is a member of the MD-2-related lipid-recognition (ML) family, and associates with RP105, a cell-surface protein that resembles Toll-like receptor 4 (TLR4). The RP105⋅MD-1 complex has been proposed to play a role in fine-tuning the innate immune response to endotoxin such as bacterial lipopolysaccharide (LPS) via TLR4⋅MD-2, but controversy surrounds its mechanism. We have used atomically detailed simulations to reveal the structural basis for ligand binding and consequent functional dynamics of MD-1 and the RP105 complex. We rationalize reports of endogenous phospholipid binding, by showing that they prevent collapse of the malleable MD-1 fold, before refining crystallographic models and uncovering likely binding modes for LPS analogs. Subsequent binding affinity calculations reveal that endotoxin specificity arises from the entropic cost of expanding the MD-1 cavity to accommodate bulky lipid tails, and support the role of MD-1 as a "sink" that sequesters endotoxin from TLR4 and stabilizes RP105/TLR4 interactions.
authors.affiliation: Department of Chemistry, Centre for Molecular Informatics, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Maite L
authors.initials: ML
authors.lastname: Ortiz-Suarez
authors.affiliation: Department of Chemistry, Centre for Molecular Informatics, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Bioinformatics Institute (A(∗)STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore. Electronic address: peterjb@bii.a-star.edu.sg.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism; D000954:Antigens, Surface / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D007108:Immune Tolerance; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; C092722:CD180 protein, human; C115213:LY86 protein, human; D008070:Lipopolysaccharides