The structure and inhibition of a GGDEF diguanylate cyclase complexed with (c-di-GMP) 2 at the active site

Chao Yu Yang, Ko Hsin Chin, Mary Lay Cheng Chuah, Zhao Xun Liang, Andrew H.J. Wang, Shan Ho Chou

研究成果: 雜誌貢獻文章同行評審

48 引文 斯高帕斯(Scopus)


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 inter-calated 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.

頁(從 - 到)997-1008
期刊Acta Crystallographica Section D: Biological Crystallography
出版狀態已發佈 - 12月 2011

ASJC Scopus subject areas

  • 結構生物學


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