Abstract
G protein-coupled receptors (GPCRs) are the largest family of membrane proteins with more than 800 members. GPCRs are involved in numerous physiological functions within the human body and are the target of more than 30% of the United States Food and Drug Administration (FDA) approved drugs. At present, over 400 experimental GPCR structures are available in the Protein Data Bank (PDB) representing 76 unique receptors. The absence of an experimental structure for the majority of GPCRs demand homology models for structure-based drug discovery workflows. The generation of good homology models requires appropriate templates. The commonly used methods for template selection are based on sequence identity. However, there exists low sequence identity among the GPCRs. Sequences with similar patterns of hydrophobic residues are often structural homologs, even with low sequence identity. Extending this, we propose a biophysical approach for template selection based principally on hydrophobicity correspondence between the target and the template. Our approach takes into consideration other relevant parameters, including resolution, similarity within the orthosteric binding pocket of GPCRs, and structure completeness, for template selection. The proposed method was implemented in the form of a free tool called Bio-GATS, to provide the user with easy selection of the appropriate template for a query GPCR sequence. Bio-GATS was successfully validated with recent published benchmarking datasets. An application to an olfactory receptor to select an appropriate template has also been provided as a case study.
Highlights
The three-dimensional (3-D) structure of the proteins is important for deciphering its biological function and gaining mechanistic insights of biological events
We proposed a biophysical approach recently for G protein-coupled receptors (GPCRs) template selection (Jabeen and Ranganathan, 2020), which was applied to an olfactory receptor (OR), based on hydrophobicity correspondence (HC), the resolution, completeness of structures, and similarity between the residues within the orthosteric binding pocket for GPCRs
We considered representative receptors from each class (A, B, C, D, and F) with known experimental structure and built their models on the basis of templates selected by Bio-GATS
Summary
The three-dimensional (3-D) structure of the proteins is important for deciphering its biological function and gaining mechanistic insights of biological events. Analyzing the relationship between sequence, structure, and function between proteins might help in transferring functional annotation between proteins. Cyrus Chothia’s contribution in incorporating computational approaches for a sequence-structure relationship, such as the development of Structural Classification of Proteins (SCOP) database (Lo Conte et al, 2000), has opened up. The hierarchical division of proteins into classes, folds, superfamilies, and families based on structural and functional similarities by SCOP has enabled linking of known protein structures with homologous sequences lacking a known structure. The success of the homology model is greatly determined by the selected template and the alignment generated between the target and the template (Wallner and Elofsson, 2005; Haddad et al, 2020). Our biophysical method for GPCR template selection is based primarily on hydrophobic correspondence (HC) between the target and the template, inspired by the work of Cyrus Chothia on the conceptual methods for hydrophobicity determination (Chothia, 1976)
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