A leucine-rich repeat assembly approach for homology modeling of the human TLR5-10 and mouse TLR11-13 ectodomains |
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Authors: | Tiandi Wei Jing Gong Shaila C Rössle Ferdinand Jamitzky Wolfgang M Heckl Robert W Stark |
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Institution: | 1.Center for Nanoscience,Ludwig-Maximilians-Universit?t München,Munich,Germany;2.Department of Earth and Environmental Sciences,Ludwig-Maximilians-Universit?t München,Munich,Germany;3.Leibniz Supercomputing Centre,Garching,Germany;4.Deutsches Museum,Munich,Germany;5.TUM School of Education,Technische Universit?t München,Munich,Germany |
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Abstract: | So far, 13 groups of mammalian Toll-like receptors (TLRs) have been identified. Most TLRs have been shown to recognize pathogen-associated
molecular patterns from a wide range of invading agents and initiate both innate and adaptive immune responses. The TLR ectodomains
are composed of varying numbers and types of leucine-rich repeats (LRRs). As the crystal structures are currently missing
for most TLR ligand-binding ectodomains, homology modeling enables first predictions of their three-dimensional structures
on the basis of the determined crystal structures of TLR ectodomains. However, the quality of the predicted models that are
generated from full-length templates can be limited due to low sequence identity between the target and templates. To obtain
better templates for modeling, we have developed an LRR template assembly approach. Individual LRR templates that are locally
optimal for the target sequence are assembled into multiple templates. This method was validated through the comparison of
a predicted model with the crystal structure of mouse TLR3. With this method, we also constructed ectodomain models of human
TLR5, TLR6, TLR7, TLR8, TLR9, and TLR10 and mouse TLR11, TLR12, and TLR13 that can be used as first passes for a computational
simulation of ligand docking or to design mutation experiments. This template assembly approach can be extended to other repetitive
proteins. |
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