Dear Mohammed,
The following is a publication describes an inhibition of diguannylate cyclase by XCC4471(GGDEF)-c-di-GMP complex:
1-Acta Crystallogr D Biol Crystallogr. 2011 Dec;67(Pt 12):997-1008. doi: 10.1107/S090744491104039X. Epub 2011 Nov 18.
The structure and inhibition of a GGDEF diguanylate cyclase complexed with (c-di-GMP)(2) at the active site.
Yang CY1, Chin KH, Chuah ML, Liang ZX, Wang AH, Chou SH.
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Abstract
Cyclic diguanosine monophosphate (c-di-GMP) is a key signalling molecule involved in regulating many important biological functions in bacteria. The synthesis of c-di-GMP is catalyzed by the GGDEF-domain-containing diguanylate cyclase (DGC), the activity of which is regulated by the binding of product at the allosteric inhibitory (I) site. However, a significant number of GGDEF domains lack the RxxD motif characteristic of the allosteric I site. Here, the structure of XCC4471(GGDEF), the GGDEF domain of a DGC from Xanthomonas campestris, in complex with c-di-GMP has been solved. Unexpectedly, the structure of the complex revealed a GGDEF-domain dimer cross-linked by two molecules of c-di-GMP at the strongly conserved active sites. In the complex (c-di-GMP)(2) adopts a novel partially intercalated form, with the peripheral guanine bases bound to the guanine-binding pockets and the two central bases stacked upon each other. Alteration of the residues involved in specific binding to c-di-GMP led to dramatically reduced K(d) values between XCC4471(GGDEF) and c-di-GMP. In addition, these key residues are strongly conserved among the many thousands of GGDEF-domain sequences identified to date. These results indicate a new product-bound form for GGDEF-domain-containing proteins obtained via (c-di-GMP)(2) binding at the active site. This novel XCC4471(GGDEF)-c-di-GMP complex structure may serve as a general model for the design of lead compounds to block the DGC activity of GGDEF-domain-containing proteins in X. campestris or other microorganisms that contain multiple GGDEF-domain proteins.
http://www.ncbi.nlm.nih.gov/pubmed/22120736
antagonize diguanylate cyclase enzymes:
2-Antimicrob Agents Chemother. 2012 Oct;56(10):5202-11. doi: 10.1128/AAC.01396-12. Epub 2012 Jul 30.
Identification of small molecules that antagonize diguanylate cyclase enzymes to inhibit biofilm formation.
Sambanthamoorthy K1, Sloup RE, Parashar V, Smith JM, Kim EE, Semmelhack MF, Neiditch MB, Waters CM.
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Abstract
Bacterial biofilm formation is responsible for numerous chronic infections, causing a severe health burden. Many of these infections cannot be resolved, as bacteria in biofilms are resistant to the host's immune defenses and antibiotic therapy. New strategies to treat biofilm-based infections are critically needed. Cyclic di-GMP (c-di-GMP) is a widely conserved second-messenger signal essential for biofilm formation. As this signaling system is found only in bacteria, it is an attractive target for the development of new antibiofilm interventions. Here, we describe the results of a high-throughput screen to identify small-molecule inhibitors of diguanylate cyclase (DGC) enzymes that synthesize c-di-GMP. We report seven small molecules that antagonize these enzymes and inhibit biofilm formation by Vibrio cholerae. Moreover, two of these compounds significantly reduce the total concentration of c-di-GMP in V. cholerae, one of which also inhibits biofilm formation by Pseudomonas aeruginosa in a continuous-flow system. These molecules represent the first compounds described that are able to inhibit DGC activity to prevent biofilm formation.
http://www.ncbi.nlm.nih.gov/pubmed/22850508
Hoping this will be helpful,
Rafik
You can find a list of inhibitors of this enzyme at one of these pages, depending on which enzyme you are interested in:
http://brenda-enzymes.org/enzyme.php?ecno=2.7.7.65#INHIBITORS
http://brenda-enzymes.org/enzyme.php?ecno=3.1.4.52#INHIBITORS
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