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Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis.

ABSTRACT: Side effects from targeted drugs remain a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and have similar structures and drug-binding pockets. To identify targetable differences between paralogs, we analyzed two types (type-I and type-II) of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors (GPCRs) at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-II amino acids were significantly enriched in the binding sites of antagonist MK-0893 to GCGR, which had a radical shift in physicochemical properties between GCGR and GLP-1R. We also examined the role of type-I amino acids between GCGR and GLP-1R. The divergent features between GCGR and GLP-1R paralogs may be helpful in their discrimination, thus enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs.

SUBMITTER: Sa Z

PROVIDER: S-EPMC5582795 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledIn order to optimize interactions with their environment and one another, bacteria regulate their motility. In the case of the rod-shaped cells of Myxococcus xanthus, regulated motility is essential for social behaviors. M. xanthus moves over surfaces using type IV pilus-dependent motility and gliding motility. These two motility systems are coordinated by a protein module that controls cell polarity and consists of three polarly localized proteins, the small G protein MglA, the cognate MglA GTPase-activating protein MglB, and the response regulator RomR. Cellular reversals are induced by the Frz chemosensory system, and the output response regulator of this system, FrzZ, interfaces with the MglA/MglB/RomR module to invert cell polarity. Using a computational approach, we identify a paralog of MglB, MXAN_5770 (MglC). Genetic epistasis experiments demonstrate that MglC functions in the same pathway as MglA, MglB, RomR, and FrzZ and is important for regulating cellular reversals. Like MglB, MglC localizes to the cell poles asymmetrically and with a large cluster at the lagging pole. Correct polar localization of MglC depends on RomR and MglB. Consistently, MglC interacts directly with MglB and the C-terminal output domain of RomR, and we identified a surface of MglC that is necessary for the interaction with MglB and for MglC function. Together, our findings identify an additional member of the M. xanthus polarity module involved in regulating motility and demonstrate how gene duplication followed by functional divergence can add a layer of control to the complex cellular processes of motility and motility regulation.ImportanceGene duplication and the subsequent divergence of the duplicated genes are important evolutionary mechanisms for increasing both biological complexity and regulation of biological processes. The bacterium Myxococcus xanthus is a soil bacterium with an unusually large genome that carries out several social processes, including predation of other bacterial species and formation of multicellular, spore-filled fruiting bodies. One feature of the large M. xanthus genome is that it contains many gene duplications. Here, we compare the products of one example of gene duplication and divergence, in which a paralog of the cognate MglA GTPase-activating protein MglB has acquired a different and opposing role in the regulation of cellular polarity and motility, processes critical to the bacterium's social behaviors.

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Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis.

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