Crystal structure and regulation mechanisms of the CyaB adenylyl cyclase from the human pathogen Pseudomonas aeruginosa.
Crystal structure and regulation mechanisms of the CyaB adenylyl cyclase from the human pathogen Pseudomonas aeruginosa.
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人类病原体铜绿假单胞菌 CyaB 腺苷酸环化酶的晶体结构和调节机制。
DOI：
10.1016/j.jmb.2011.12.045
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发表时间：
2012
影响因子：
5.6
通讯作者：
Steegborn,Clemens
中科院分区：
文献类型：
--
作者：
Topal,Hüsnü;Fulcher,NanetteB;Bitterman,Jacob;Salazar,Eric;Buck,Jochen;Levin,LonnyR;Cann,MartinJ;Wolfgang,MatthewC;Steegborn,Clemens
Pseudomonas aeruginosa is an opportunistic bacterial pathogen and a major cause of healthcare-associated infections. While the organism's intrinsic and acquired resistance to most antibiotics hinders treatment of P. aeruginosa infections, the regulatory networks controlling its virulence provide novel targets for drug development. CyaB, a key regulator of P. aeruginosa virulence, belongs to the Class III adenylyl cyclase (AC) family of enzymes that synthesize the second messenger cyclic adenosine 3′,5′-monophosphate. These enzymes consist of a conserved catalytic domain fused to one or more regulatory domains. We describe here the biochemical and structural characterization of CyaB and its inhibition by small molecules. We show that CyaB belongs to the Class IIIb subfamily, and like other subfamily members, its activity is stimulated by inorganic carbon. CyaB is also regulated by its N-terminal MASE2 (membrane-associated sensor 2) domain, which acts as a membrane anchor. Using a genetic screen, we identified activating mutations in CyaB. By solving the crystal structure of the CyaB catalytic domain, we rationalized the effects of these mutations and propose that CyaB employs regulatory mechanisms similar to other Class III ACs. The CyaB structure further indicates subtle differences compared to other Class III ACs in both the active site and the inhibitor binding pocket. Consistent with these differences, we observed a unique inhibition profile, including identification of a CyaB selective compound. Overall, our results reveal mechanistic details of the physiological and pharmacological regulation of CyaB and provide the basis for its exploitation as a therapeutic drug target.
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DOI：
10.1073/pnas.95.23.13899
发表时间：
1998-11-10
影响因子：
11.1
作者：
Yahr, TL;Vallis, AJ;Frank, DW
通讯作者：
Frank, DW
腺苷酸环化酶：一类异质的 ATP 利用酶。
DOI：
10.1016/s0079-6603(08)60052-5
发表时间：
1994
期刊：
Progress in nucleic acid research and molecular biology
影响因子：
--
作者：
Octavian Bârzu;Antoine Danchin
通讯作者：
Antoine Danchin
DOI：
--
发表时间：
--
期刊：
--
影响因子：
--
作者：
A. Mccoy;R. Grosse-Kunstleve;L. C. Storoni;R. Read
通讯作者：
A. Mccoy;R. Grosse-Kunstleve;L. C. Storoni;R. Read
二氧化碳对哺乳动物 G 蛋白反应性腺苷酸环化酶的刺激
影响因子：
4.8
作者：
Philip D. Townsend;Phillip M. Holliday;Stepan Fenyk;K. Hess;M. Gray;David R. W. Hodgson;M. Cann
通讯作者：
M. Cann
影响因子：
6.7
作者：
Hall RA;De Sordi L;Maccallum DM;Topal H;Eaton R;Bloor JW;Robinson GK;Levin LR;Buck J;Wang Y;Gow NA;Steegborn C;Mühlschlegel FA
通讯作者：
Mühlschlegel FA