Journal
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Volume 67, Issue 4, Pages 950-960Publisher
WILEY-LISS
DOI: 10.1002/prot.21251
Keywords
glycine receptor; ligand-gated ion channel; ligand binding domain; nicotinicoid receptor; cys-loop receptor; protein structure modeling; protein structure prediction; ligand docking; alphal subunit
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Funding
- NIGMS NIH HHS [R01 GM067962-04, R01 GM067962] Funding Source: Medline
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We present a homology based model of the ligand binding domain (LBD) of the homopentameric alphal glycine receptor (GlyR). The model is based on multiple sequence alignment with other members of the nicotinicoid ligand gated ion channel superfamily and two homologous acetylcholine binding proteins (AChBP) from the freshwater (Lymnaea stagnalis) and saltwater (Aplysia californica) snails with known high resolution structure. Using two template proteins with known structure to model three dimensional structure of a target protein is especially advantageous for sequences with low homology as in the case presented in this paper. The final model was cross-validated by critical evaluation of experimental and published mutagenesis, functional and other biochemical studies. In addition, a complex structure with strychnine antagonist in the putative binding site is proposed based on docking simulation using Autodock program. Molecular dynamics (MD) simulations with simulated annealing protocol are reported on the proposed LBD of GlyR, which is stable in 5 ns simulation in water, as well as for a deformed LBD structure modeled on the corresponding - domain determined in low-resolution cryomicroscopy structure of the alpha subunit of the full-length acetylcholine receptor (AChR). Our simulations demonstrate that the beta-sandwich central core of the protein monomer is fairly rigid in the simulations and resistant to deformations in water. Proteins 2007;67:950-960. (C) 2007 Wiley-Liss, Inc.
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