Cooperative Substrate Binding by a Diguanylate Cyclase

Oliveira, Maycon C.; Teixeira, Ricardo Henrique de Oliveira Braga; Andrade, Maxuel O.; Pinheiro, Gláucia M.S.; Ramos, Carlos H.I.; Farah, Chuck S.

doi:10.1016/j.jmb.2014.11.012

Cited by 25 publications

(29 citation statements)

References 73 publications

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“…Surface-associated bacteria usually harbor more c-di-GMP regulators than free-living bacteria, presumably as an adaptive strategy (120). O 2 , H 2 O 2 , NO, redox potential, light, sucrose, amino acids, polyamines (such as norspermidine and spermidine), Zn 2ϩ , bile acids, bicarbonate, indole, QS autoinducers, cis-2-dodecenoic acid and cis-11-methyl-dodecenoic acid (unsaturated fatty acids that serve as bacterial diffusible signal factors), and nutritional conditions that cause starvation (or depletion of a specific carbon source such as glucose or glycerol) have been identified as environmental cues that induce the bacterial response via altering the intracellular c-di-GMP concentration (480,(492)(493)(494)(495)(496)(497)(498)(499)(500)(501)(502)(503)(504)(505)(506)(507)(508). However, the vast majority of the environmental signals that modulate the activity of the DGCs and PDEs remain unidentified.…”

Section: Centralized Regulation By Second Messengersmentioning

confidence: 99%

Microbial Surface Colonization and Biofilm Development in Marine Environments

Dang

Lovell

2016

Microbiol Mol Biol Rev

872

636

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SUMMARYBiotic and abiotic surfaces in marine waters are rapidly colonized by microorganisms. Surface colonization and subsequent biofilm formation and development provide numerous advantages to these organisms and support critical ecological and biogeochemical functions in the changing marine environment. Microbial surface association also contributes to deleterious effects such as biofouling, biocorrosion, and the persistence and transmission of harmful or pathogenic microorganisms and their genetic determinants. The processes and mechanisms of colonization as well as key players among the surface-associated microbiota have been studied for several decades. Accumulating evidence indicates that specific cell-surface, cell-cell, and interpopulation interactions shape the composition, structure, spatiotemporal dynamics, and functions of surface-associated microbial communities. Several key microbial processes and mechanisms, including (i) surface, population, and community sensing and signaling, (ii) intraspecies and interspecies communication and interaction, and (iii) the regulatory balance between cooperation and competition, have been identified as critical for the microbial surface association lifestyle. In this review, recent progress in the study of marine microbial surface colonization and biofilm development is synthesized and discussed. Major gaps in our knowledge remain. We pose questions for targeted investigation of surface-specific community-level microbial features, answers to which would advance our understanding of surface-associated microbial community ecology and the biogeochemical functions of these communities at levels from molecular mechanistic details through systems biological integration.

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Section: Centralized Regulation By Second Messengersmentioning

confidence: 99%

Microbial Surface Colonization and Biofilm Development in Marine Environments

Dang

Lovell

2016

Microbiol Mol Biol Rev

872

636

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“…Interactions between the EAL domain protein YciR and diguanylate cyclase YdaM control a key step in E. coli biofilm formation through a suggested modulation of localized cyclic di-GMP levels (34). Functionality is also provided, however, by specific protein-protein interactions that are independent of the catalytic activity (19,35). In this case, the XXDXDX motif, which is highly conserved in GGDEF domains, is required for the interaction with the HD-GYP domain.…”

Section: Specificity In Regulatory Actionmentioning

confidence: 99%

“…Recent experimentally characterized proteins with a G¡A or G¡S substitution still exhibit significant functionality, demonstrating unexpected flexibility in the GGDEF containing active-site hairpin ( Fig. 2) (17)(18)(19).…”

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confidence: 99%

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Progress in Understanding the Molecular Basis Underlying Functional Diversification of Cyclic Dinucleotide Turnover Proteins

2017

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Cyclic di-GMP was the first cyclic dinucleotide second messenger described, presaging the discovery of additional cyclic dinucleotide messengers in bacteria and eukaryotes. The GGDEF diguanylate cyclase (DGC) and EAL and HD-GYP phosphodiesterase (PDE) domains conduct the turnover of cyclic di-GMP. These three unrelated domains belong to superfamilies that exhibit significant variations in function, and they include both enzymatically active and inactive members, with a subset involved in synthesis and degradation of other cyclic dinucleotides. Here, we summarize current knowledge of sequence and structural variations that underpin the functional diversification of cyclic di-GMP turnover proteins. Moreover, we highlight that superfamily diversification is not restricted to cyclic di-GMP signaling domains, as particular DHH/DHHA1 domain and HD domain proteins have been shown to act as cyclic di-AMP phosphodiesterases. We conclude with a consideration of the current limitations that such diversity of action places on bioinformatic prediction of the roles of GGDEF, EAL, and HD-GYP domain proteins.KEYWORDS cyclic dinucleotide second messenger, GGDEF domain, EAL domain, HD-GYP domain, DHH/DHHA1 domain, cyclic GAMP, cyclic di-AMP, cyclic di-GMP, second messenger T he dinucleotide cyclic di-GMP is the most abundant second messenger in bacteria. It promotes the environmental lifestyle switch between sessility and motility, as well as the host-related lifestyle switch between acute and chronic/benign infection. A hallmark of the cyclic di-GMP signaling network is an apparent redundancy of cyclic di-GMP turnover proteins encoded in one genome. However, many of these proteins have distinct N-terminal sensing and signaling domains, suggesting that their activities in cyclic di-GMP turnover respond posttranslationally to various (and different) intraand extracellular signals. In gross terms, the number of cyclic di-GMP turnover proteins is linearly correlated with genome size within the different bacterial phyla, with Thermotogae having one of the highest cyclic di-GMP-related "IQs," the density of enzymes per megabase pair, with some species harboring over 100 cyclic di-GMP turnover proteins (http://www.ncbi.nlm.nih.gov/Complete_Genomes/c-di-GMP.html). As in other domain superfamilies, extensive sequence diversity exists. Here, we review the knowledge on the translation of sequence diversity of cyclic di-GMP turnover proteins into functional diversity. We conclude by discussing whether and how a unified nomenclature for cyclic di-GMP turnover proteins can be established.

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“…As previously reported (11,26), the standard Michaelis-Menten kinetic scheme is inadequate for the kinetic profile of GGDEF enzymes, and therefore, the corresponding inhibition profile could not be informative. In order to bypass this limitation, we designed a FRET-based displacement experiment aimed at demonstrating qualitatively that inhibitor 7 competes for the GTP binding site.…”

Section: Virtual Screening For Identification Of Novel Pled Inhibitorsmentioning

confidence: 92%

In Silico Discovery and In Vitro Validation of Catechol-Containing Sulfonohydrazide Compounds as Potent Inhibitors of the Diguanylate Cyclase PleD

et al. 2016

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Biofilm formation is responsible for increased antibiotic tolerance in pathogenic bacteria. Cyclic di-GMP (c-di-GMP) is a widely used second-messenger signal that plays a key role in bacterial biofilm formation. c-di-GMP is synthesized by diguanylate cyclases (DGCs), a conserved class of enzymes absent in mammals and hence considered attractive molecular targets for the development of antibiofilm agents. Here, the results of a virtual screening approach aimed at identifying small-molecule inhibitors of the DGC PleD from Caulobacter crescentus are described. A three-dimensional (3D) pharmacophore model, derived from the mode of binding of GTP to the active site of PleD, was exploited to screen the ZINC database of compounds. Seven virtual hits were tested in vitro for their ability to inhibit the activity of purified PleD by using circular dichroism spectroscopy. Two druglike molecules with a catechol moiety and a sulfonohydrazide scaffold were shown to competitively inhibit PleD at the low-micromolar range (50% inhibitory concentration [IC 50 ] of ϳ11 M). Their predicted binding mode highlighted key structural features presumably responsible for the efficient inhibition of PleD by both hits. These molecules represent the most potent in vitro inhibitors of PleD identified so far and could therefore result in useful leads for the development of novel classes of antimicrobials able to hamper biofilm formation. IMPORTANCEBiofilm-mediated infections are difficult to eradicate, posing a threatening health issue worldwide. The capability of bacteria to form biofilms is almost universally stimulated by the second messenger c-di-GMP. This evidence has boosted research in the last decade for the development of new antibiofilm strategies interfering with c-di-GMP metabolism. Here, two potent inhibitors of c-di-GMP synthesis have been identified in silico and characterized in vitro by using the well-characterized DGC enzyme PleD from C. crescentus as a structural template and molecular target. Given that the protein residues implied as crucial for enzyme inhibition are found to be highly conserved among DGCs, the outcome of this study could pave the way for the future development of broad-spectrum antibiofilm compounds.

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Cooperative Substrate Binding by a Diguanylate Cyclase

Cited by 25 publications

References 73 publications

Microbial Surface Colonization and Biofilm Development in Marine Environments

Microbial Surface Colonization and Biofilm Development in Marine Environments

Progress in Understanding the Molecular Basis Underlying Functional Diversification of Cyclic Dinucleotide Turnover Proteins

In Silico Discovery and In Vitro Validation of Catechol-Containing Sulfonohydrazide Compounds as Potent Inhibitors of the Diguanylate Cyclase PleD

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