GPCRs, G-proteins, effectors and their interactions: human-gpDB, a database employing visualization tools and data integration techniques

Abstract

G-protein coupled receptors (GPCRs) are a major family of membrane receptors in eukaryotic cells. They play a crucial role in the communication of a cell with the environment. Ligands bind to GPCRs on the outside of the cell, activating them by causing a conformational change, and allowing them to bind to G-proteins. Through their interaction with G-proteins, several effector molecules are activated leading to many kinds of cellular and physiological responses. The great importance of GPCRs and their corresponding signal transduction pathways is indicated by the fact that they take part in many diverse disease processes and that a large part of efforts towards drug development today is focused on them. We present Human-gpDB, a database which currently holds information about 713 human GPCRs, 36 human G-proteins and 99 human effectors. The collection of information about the interactions between these molecules was done manually and the current version of Human-gpDB holds information for about 1663 connections between GPCRs and G-proteins and 1618 connections between G-proteins and effectors. Major advantages of Human-gpDB are the integration of several external data sources and the support of advanced visualization techniques. Human-gpDB is a simple, yet a powerful tool for researchers in the life sciences field as it integrates an up-to-date, carefully curated collection of human GPCRs, G-proteins, effectors and their interactions. The database may be a reference guide for medical and pharmaceutical research, especially in the areas of understanding human diseases and chemical and drug discovery. Database URLs: http://schneider.embl.de/human_gpdb; http://bioinformatics.biol.uoa.gr/human_gpdb/

Figure 1.

Over view of Human-gpDB web application. (a) Backend of the application consisting of manually collected information regarding GPCRs, G-proteins, effectors and their interactions as well as a wide range of publicly available information for each of these proteins stored in a MySQL database (‘Data Integration’ section for more details). (b) A CGI-Perl script handles the communication between the client and the server and (c) provides a wide range of information as output to the user (see ‘Utility’ section for more details). The system can be coupled with (d) a 2D visualization tool (Medusa) and a 3D visualization tool (Arena3D), which allows the easy visualization of the relationships between GPCRs, G-Proteins, effectors and the drugs (see ‘Visualization’ sections for more details).

Figure 2.

Visualization of human Bradykinin B2 receptor’s interactions (a) Arena3D Visualization: human Bradykinin B2 receptor targets six different subfamilies of Gα G-Proteins belonging to Gα-q/11 and Gα-12/13 families. The G-Proteins are connected to 22 different types of effectors belonging to nine families. (b) Medusa 2D Visualization: human Bradykinin B2 receptor targets Gα G-Proteins belonging to six distinct Gα subfamilies (Gα-q, Gα-11, Gα-14, Gα-15/16, Gα-12 and Gα-13). These Gα G-Proteins interact with 22 types of effectors.

Figure 3.

Visualization of human Dopamine D5 receptor’s interactions. (a) Arena3D Visualization: Human Dopamine D5 receptor targets two Gα-s G-Proteins. The G-Proteins are connected to 12 types of effectors belonging to four specific families. These are: Adenylate cyclases, Regulators of G-Protein signaling, Tyr protein kinases and tubulins. (b) Medusa 2D Visualization: human dopamine D5 receptor targets Gα-s G-Proteins, which interact with the following four families of effectors: Adenylate cyclases, Regulators of G-Protein signaling, Tyr protein kinases and tubulins.

Figure 4.

Visualization of human Rhodopsin receptors’ interactions. (a) Arena3D Visualization: Human Rhodopsin receptor targets three Gα G-Proteins that belong to the Gα-t subfamily. The three G-Proteins interact with five effectors belonging to the Rhodopsin-sensitive cGMP-specific PDEases subfamily and more specifically to Phosphodiesterase 6 type of effectors. (b) Medusa 2D Visualization: the Rhodopsin subfamily of the Opsin/Rhodopsin family of the Class A of the GPCRs interacts with the Gα-t subfamily of the G-Proteins which interact with the Rhodopsin-sensitive cGMP-specific PDEases effectors’ subfamily.

Figure 5.

Visualization of human Prostanoid TP receptor’s interactions (drugs included). (a) Arena3D Visualization: Human Prostanoid TP receptor protein of Class A GPCR family targets four Gα G-Proteins that belong to G_q/11 family. The G-Proteins are connected to effectors proteins belonging to eight specific families. For this specific receptor 23 different drugs exist. (b) Medusa 2D Visualization: Human Prostanoid TP receptor protein targets Gα G-Proteins that belong to G_q/11 family. These G-Proteins interact with 11 different subfamilies of effectors. For this specific receptor 23 different drugs exist.

Figure 6.

Visualization of human Glucoprotein Hormone TSH receptors’ interactions. (a) Arena3D Visualization: Human Glucoprotein Hormone TSH receptor targets 13 G-Proteins of 10 different subfamilies, which belong to all four Gα families. These G-proteins target 16 different families of effectors. (b) Medusa 2D Visualization: Human Glucoprotein Hormone TSH receptor targets 13 Gα G-Proteins from all four Gα families. More accurately, these Gα G-Proteins belong to 10 respective Gα subfamilies and interact with 19 subfamilies of effectors.