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Review
. 2021 Jun 7;16(11):1696-1715.
doi: 10.1002/cmdc.202100039. Epub 2021 Mar 22.

Strategies towards Targeting Gαi/s Proteins: Scanning of Protein-Protein Interaction Sites To Overcome Inaccessibility

Britta Nubbemeyer  1 , Anna Pepanian  1 , Ajay Abisheck Paul George  2 , Diana Imhof  1
Affiliations
Review

Strategies towards Targeting Gαi/s Proteins: Scanning of Protein-Protein Interaction Sites To Overcome Inaccessibility

Britta Nubbemeyer et al. ChemMedChem. .

Abstract

Heterotrimeric G proteins are classified into four subfamilies and play a key role in signal transduction. They transmit extracellular signals to intracellular effectors subsequent to the activation of G protein-coupled receptors (GPCRs), which are targeted by over 30 % of FDA-approved drugs. However, addressing G proteins as drug targets represents a compelling alternative, for example, when G proteins act independently of the corresponding GPCRs, or in cases of complex multifunctional diseases, when a large number of different GPCRs are involved. In contrast to Gαq, efforts to target Gαi/s by suitable chemical compounds has not been successful so far. Here, a comprehensive analysis was conducted examining the most important interface regions of Gαi/s with its upstream and downstream interaction partners. By assigning the existing compounds and the performed approaches to the respective interfaces, the druggability of the individual interfaces was ranked to provide perspectives for selective targeting of Gαi/s in the future.

Keywords: G alpha proteins; peptides; protein-protein interactions; signal transduction; small molecules.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Involvement of GPCRs and G proteins in human diseases and drug development. A) Distribution of approved drugs (small molecules and biologics) per human protein family class derived from Santos et al. [15] B) Putative primary Gα protein coupling, based on the classification of GPCR signaling according to Sriram et al. [5] C) Involvement of Gαi/s subfamilies in multiple disorders such as cancer, heart failure, endocrine disorders or thrombosis, adapted from Li et al. [1]
Figure 2
Figure 2
Structural features of Gα proteins: Contact areas to the GPCRs (green), Gβγ (blue), effectors (yellow) and accessory proteins (red, most common areas depicted) within the GDP‐bound (violet) Gαi1 homology model (from PDB IDs: 3UMS [54] and 5JS8 [55] ).
Figure 3
Figure 3
Contacts of Gα to bound nucleotides. Gαt crystal structures (GDP‐bound: PDB ID: 1TAG [52] (A), GTPγS‐bound: PDB ID: 1TND [51] (C), nucleotides in violet), domain arrangement [84] of Gα proteins (B) and contacts of nucleotides (D) to the P‐loop (blue), RXXTXGI (yellow), DXXG (orange), NKXD (green), TCAT (red), helical domain (cyan) are shown. Dotted lines indicate hydrogen bonds and grey bars van der Waals interactions. Residues are named according to the crystal structures.
Figure 4
Figure 4
Natural compounds targeting the Gα‐GPCR interface. A) Modification of Gαi by pertussis toxin (PTX) derived from Mangmool et al. [129] PTX transfers the ADP‐ribose element from nicotinamide adenine dinucleotide (NAD+) to Gαi CysG.H5.23. B) Crystal structure of PTX (gray, PDB ID: 1PRT [128] ). The S1 subunit (magenta) is important for Gαi inhibition. C) G protein‐bound NMR structure ensemble (14 structures) of mastoparan‐X (H‐INWKGIAAMAKKLL‐NH2, PDB ID: 1 A13 [133] ).
Figure 5
Figure 5
Chemical structures of suramin (1) and its analogues: NF449 (2) and NF503 (3).[ 1 , 180 , 181 ]
Figure 6
Figure 6
Natural compounds targeting the Gα‐accessory protein interface. A) Modification of Gαs by cholera toxin (CTX). CTX transfers the ADP‐ribose element from nicotinamide adenine dinucleotide (NAD+) to ArgG.hfs2.2 of Gαs, thereby inhibiting GTP hydrolysis. B) Modification of Gαi by P. multocida toxin (PMT). PMT catalyzes the deamidation of GlnG.s3h2.3 to GluG.s3h2.3 and thus inhibits GTP hydrolysis. C) Crystal structures (gray) of cholera toxin (CTX, PDB ID: 1XTC [213] ), heat‐labile enterotoxin (HLT, PDB ID: 1LTS [207] ), P. multocida toxin (PMT, PDB ID: 2EC5 [214] ) and the P. asymbiotica protein toxin (PaTox) glycosyltransferase domain (PDB ID: 4MIX [212] ) in complex with UDP‐GlcNAc (violet).
Figure 7
Figure 7
Chemical structures of small molecules targeting the Gα‐accessory protein interface. Imidazopyrazine derivatives BIM‐46174 (4) and BIM‐46187 (5), [11] compounds 0990 (6) and 4630 (7), [223] aurintricarboxylic acid (ATA, 8) and suramin derivative NF023 (9). [188]
Figure 8
Figure 8
Chemical structures of mRNA display‐derived peptides targeting the Gα accessory protein interface. The peptides cycGiBP (10), [233] cycPRP‐1 (11), cycPRP‐3 (12), [234] and Gα SUPR (13) [235] are Gαi1⋅GDP selective. GsNI‐1 (14) [217] is Gαs⋅GTP selective.
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