title: Homology modeling of human Toll-like receptors TLR7, 8, and 9 ligand-binding domains.
abstract: Toll-like receptors (TLRs) play a key role in the innate immune system. The TLR7, 8, and 9 compose a family of intracellularly localized TLRs that signal in response to pathogen-derived nucleic acids. So far, there are no crystallographic structures for TLR7, 8, and 9. For this reason, their ligand-binding mechanisms are poorly understood. To enable first predictions of the receptor-ligand interaction sites, we developed three-dimensional structures for the leucine-rich repeat ectodomains of human TLR7, 8, and 9 based on homology modeling. To achieve a high sequence similarity between targets and templates, structural segments from all known TLR ectodomain structures (human TLR1/2/3/4 and mouse TLR3/4) were used as candidate templates for the modeling. The resulting models support previously reported essential ligand-binding residues. They also provide a basis to identify three potential receptor dimerization mechanisms. Additionally, potential ligand-binding residues are identified using combined procedures. We suggest further investigations of these residues through mutation experiments. Our modeling approach can be extended to other members of the TLR family or other repetitive proteins.
authors.affiliation: Department of Earth and Environmental Sciences, Center for Nanoscience, Ludwig-Maximilians-Universität München, 80333 Munich, Germany.
authors.forename: Tiandi
authors.initials: T
authors.lastname: Wei
authors.forename: Jing
authors.initials: J
authors.lastname: Gong
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Jamitzky
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Heckl
authors.forename: Robert W
authors.initials: RW
authors.lastname: Stark
authors.forename: Shaila C
authors.initials: SC
authors.lastname: Rössle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary / Q000502:physiology; D016415:Sequence Alignment; D051199:Toll-Like Receptor 7 / Q000737:chemistry / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000737:chemistry / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9