Hot Spots for Agonists, Antagonists in Family A members


This study, published about four months ago, worths being highlighted.

Chemogenomic Analysis of G-Protein Coupled Receptors and Their Ligands Deciphers Locks and Keys Governing Diverse Aspects of Signalling

J.D. Wichard, A. ter Laak, G. Krause, N. Heinrich, R. Kühne, G. Kleinau.
PLosOne 6(2): e16811.


Briefly, they have gathered 100 Family A. GPCRs with known ligands and G-protein association from IUPHAR database. In total of 1664 receptor-ligand pairs including 767 full agonists, 184 partial agonists and 713 antagonists were considered. They have then looked into statistical interdependence between two variables: chemical properties of ligands and amino acid residues in the GPCRs

By an information-based approach, they have demonstrated that the extracellular domains are likely involved in either antagonistic or agonistic effects, whereas ECL2 and TM2/3 are more likely involved in agonistic action, and targeting at the top of TM5/6 may favour antagonistic action. The residues likely participate in the actions were shown with Ballesteros-Weinstein numbering scheme in rhodopsin crystal structure (Figure 3, colour-coded as in Figure 2, in their paper). Also presented was the frequency of chemical properties for antagonists and agonists for those GPCRs in their Figure 4.

In their analysis, G-protein preferences encoded in protein sequences were looked into, and the results were mapped onto Rhodopsin figure (Figure 6, colour-coded as in Figure 5). They have correlated G-protein coupling preferences extensively with the upper region of the TM domains, enabling to relate ligand binding to the effector activation.

Technical points: The mutual dependency of random variables were quantified as mutual information in estimating theoretical entropy (see the original publication for equations, the approximation method for systematic errors, and the significance test in Gaussian distribution).

Their result of multiple sequence alignment through a profile HMM as in HMMER is available to download at Dr. R. Kühne’s webpage in Leibniz-Institut für Molekulare Pharmakologie.