CADD

Short Presentation of GPCR-IFP

To start...

The purpose of the GPCR-IFP is to analyze features of G protein-coupled receptor crystal structures. There is requested to understand how ligands interact with orthosteric binding site of the receptor. The drug development processes usually cost several years and often end up in the failure of drug candidates. GPCR-IFP provides first-step drug development apprehension and, we present here all functionalities given by the server.

First, we must submit validly and analyzed (checkable in the database) receptor name or PDB code. We chose the serotonin receptors; the label of these receptors starts as "5HT", eight suggestions are displayed on the server. We focused on serotonin receptors 2B (5HT2B) have both agonist and antagonist ligands.

Figure 1: Homepage search

After clicking on the "view" button, the homepage will redirect to the results page.

Global receptor results

The results page is divided into three sections. The first section is the related structures of the receptor. The second section is the 3D visualization, in which users can display structures into cartoon or stick representations. There are no ligands represented due to slipped errors when aligning the structures. These structures are colored in unique colors to facilitate recognition. The last section is the radar charts with all interactions calculated by PLIP. Thus, one for the sum of residues interacting (named "all") and eight for specific interactions. As you can see, the agonist and antagonist bound structures are viewed into two windows, either the first, second, or last section.

Figure 2-1: List of structures belongs to related receptor

Figure 2-2: Viewer of antagonist-bound structures and agonist-bound structures

Figure 2-3: Radar chart of agonist-receptor interaction (red) and antagonist-receptor interaction (green)

The 5HT2B contains eight structures in total, including five structures binding to an agonist ligand and three structures binding to an antagonist ligand. In addition, the superimposition of structures by ligand type seems to be aligned correctly whose N-ter and C-ter ends and loops have a higher discrepancy. The residues involved in the whole set of interactions have been particularly equivalent in both type ligand structures for residues in high frequency while lower frequency residues are not necessarily found in both radar plots.

Specific structure results

The last page of results concerns a specific structure, which means a particular PDB. Here, we select 4IB4, for instance. As in the previous page, the 3D visualization representation and the 2D plots are also implemented on this page. The receptor structure, ligand structure, and interaction type representation are formalized in the 3D visualization. The users can opt the receptor and the ligand representation they request, also display the type of interaction they need. The 2D plots have two formats, the snake plot and the 2D interaction diagram. The first one is the receptor structure representation in which residues colored in red are interacting residues. Only the residues in transmembrane domains are displayed, and interacting residues in loops are thus not visible. The 2D interaction diagram shows the integral structure of the ligand; the binding line appears between the interacting atoms of the ligand and those of the protein.

Figure 3-1: Representation of specific ligand-receptor complex

Figure 3-2: Snake plot and 2D interaction diagram

The interaction between the ligand and the receptor have many hydrophobic interactions (red) and certain hydrogen bond (white), water bridges (blue), and pi stacks (green). The 2D diagram performs solely four types of interactions: hydrophobic interactions, hydrogen bond, pi type interactions (pi-stacks and pi-cation), and metal complexes. Nevertheless, the pi type interaction is unfound in the plot. The binding pocket is commonly hydrophobic which these results are thus adequate.

Interactions in master functionnalities: PLIP [1]

Interactions in 2D interaction diagram: Poseview [2]

Server databases

A. Receptors database

The receptors database include all receptors studied in this server with indicating suitable experimental structures. Furthermore, all present ligands are orthosteric ligands, so we categorize into two types of ligands: antagonist (orthosteric antagonist) and agonist (inverse ligands, partial agonist, full agonist) ligands. To get more information about the receptor, you can head to "Further information" button with some links to the PDB page. You can visualize these structure by clicking on the receptor name (protein column).




Figure 4: Receptors database page

B. Complexes database

The complexes database is more related to specific experimental structures (receptor and its ligand). You can visualize the three-dimensional structure of by clicking directly on the PDB code This page, unlike the receptor database, is listed all structures. It shows more details (unfinished setup) of the structure and the ligand.

Figure 5: Complexes database page

... to finish !

Find all additional information on the citation page. If you have any requests or else, please find the contact addresses on the contact page.


References

[1] Adasme M F, Linnemann K L, Bolz S N, Kaiser F, Salentin S, Haupt V J and Schroeder M 2021 PLIP 2021: expanding the scope of the protein–ligand interaction profiler to DNA and RNA - Nucleic Acids Research - 49 W530–4.
https://doi.org/10.1093/nar/gkab294

[2] Stierand K, Maaß P C and Rarey M 2006 Molecular complexes at a glance: automated generation of two-dimensional complex diagrams - Bioinformatics - 22 1710–6.
https://doi.org/10.1093/bioinformatics/btl150