A Web Server for GPCR-GPCR Interaction Pair Prediction

Abstract

The GGIP web server (https://protein.b.dendai.ac.jp/GGIP/) provides a web application for GPCR-GPCR interaction pair prediction by a support vector machine. The server accepts two sequences in the FASTA format. It responds with a prediction that the input GPCR sequence pair either interacts or not. GPCRs predicted to interact with the monomers constituting the pair are also shown when query sequences are human GPCRs. The server is simple to use. A pair of amino acid sequences in the FASTA format is pasted into the text area, a PDB ID for a template structure is selected, and then the ‘Execute’ button is clicked. The server quickly responds with a prediction result. The major advantage of this server is that it employs the GGIP software, which is presently the only method for predicting GPCR-interaction pairs. Our web server is freely available with no login requirement. In this article, we introduce some application examples of GGIP for disease-associated mutation analysis.

The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: potential relevance for brain and behavior

“…An extensive literature now supports the fact that Class A and B GPCRs function not only as monomeric entities but can crosstalk with other GPCRs and can even form dimers or higher-order oligomers (Terrillon and Bouvier, 2004 ; Borroto-Escuela et al, 2012 , 2014 ; Schellekens et al, 2013a ; Navarro et al, 2018 ; Milligan et al, 2019 ; Nemoto et al, 2022 ). In particular, the OXTR has been reported to be able to form homomers (Cottet et al, 2010 ; Busnelli et al, 2016 ) as well as to form dimers with other GPCRs, including with the highly related vasopressin V1a and V1b (Terrillon et al, 2003 ), the GHSR (Wallace Fitzsimons et al, 2019 ), the D2 (de la Mora et al, 2016 ), the 5HT2A (Chruścicka et al, 2019 ) and the 5HT2C (Chruścicka et al, 2021 ; Figures 1 , 2 ).…”

“…In addition, single cell co-expression analysis using mouse and human cortical data from the Allen Brain Atlas has brought some translational validation of potential GPCR co-expression. Computational approaches for modeling and predicting GPCR dimerization have been provided by the GGIP web server (Nemoto et al, 2022 ) and online resources including the GPCR-HetNet (Borroto-Escuela et al, 2014 ). The relevance of GPCR heterodimerization in vivo has been discussed in the past.…”

Orphan G protein-coupled receptors: the ongoing search for a home

“…In another possibility, conditional heteromerization of related GPCRs can result in novel functionality through allostery, as depicted by the melatonin MT1 receptor with its fellow orphan GPR50; which negatively inhibits melatonin-mediated signaling (Levoye et al, 2006;Ahmad et al, 2015). An online application for predicting GPCR-GPCR interaction pairs is offered by the GGIP web server (Nemoto et al, 2022). This tool could potentially be used to predict the possibility of a given orphan receptor engaging in dimeric complexes with other GPCR members.…”

Decrypting orphan GPCR drug discovery via multitask learning

“…Consequentially, another direction was regression models of GPCR-ligand pair activity by using ligand-based and structural docking-based machine learning algorithms [ 14 – 16 ], and the stereo-based training methods using reported protein data bank (PDB) structures and molecular structures, such as pdCSM-GPCR [ 17 ], and neural network models using voxelization of GPCR and ligand structures [ 15 ]. The third direction was the protein–protein interaction models of higher-order GPCR molecular complexes with the other GPCR protein pairs [ 18 , 19 ]. The development of orphan GPCR-targeted drugs is challenging due to the complex and diverse nature of the GPCR family.…”