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Mechanistic insight into how multidrug resistant Acinetobacter baumannii response regulator AdeR recognizes an intercistronic region

(2017) NUCLEIC ACIDS RESEARCH. 45(16). p.9773-9787
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Abstract
AdeR-AdeS is a two-component regulatory system, which controls expression of the adeABC efflux pump involved in Acinetobacter baumannii multidrug resistance. AdeR is a response regulator consisting of an N-terminal receiver domain and a C-terminal DNA-binding-domain. AdeR binds to a direct-repeat DNA in the intercistronic region between adeR and adeABC. We demonstrate a markedly high affinity binding between unphosphorylated AdeR and DNA with a dissociation constant of 20 nM. In addition, we provide a 2.75 angstrom crystal structure of AdeR DNA-binding-domain complexed with the intercistronic DNA. This structure shows that the alpha 3 and beta hairpin formed by beta 5-beta 6 interacts with the major and minor groove of the DNA, which in turn leads to the introduction of a bend. The AdeR receiver domain structure revealed a dimerization motif mediated by a gearwheel-like structure involving the D108F109-R122 motif through cation pi stack interaction. The structure of AdeR receiver domain bound with magnesium indicated a conserved Glu19Asp20-Asp63 magnesium-binding motif, and revealed that the potential phosphorylation site Asp63(OD1) forms a hydrogen bond with Lys112. We thus dissected the mechanism of how AdeR recognizes the intercistronic DNA, which leads to a diverse mode of response regulation. Unlocking the AdeRS mechanism provides ways to circumvent A. baumannii antibiotic resistance.
Keywords
2-COMPONENT SIGNAL-TRANSDUCTION, MOLECULAR-REPLACEMENT, DNA-BINDING, DOMAIN, TIGECYCLINE, ACTIVATION, SYSTEM, ADEABC, OVEREXPRESSION, EPIDEMIOLOGY

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Chicago
Wen, Yurong, Zhenlin Ouyang, Yue Yu, Xiaorong Zhou, Yingmei Pei, Bart Devreese, Paul G Higgins, and Fang Zheng. 2017. “Mechanistic Insight into How Multidrug Resistant Acinetobacter Baumannii Response Regulator AdeR Recognizes an Intercistronic Region.” Nucleic Acids Research 45 (16): 9773–9787.
APA
Wen, Y., Ouyang, Z., Yu, Y., Zhou, X., Pei, Y., Devreese, B., Higgins, P. G., et al. (2017). Mechanistic insight into how multidrug resistant Acinetobacter baumannii response regulator AdeR recognizes an intercistronic region. NUCLEIC ACIDS RESEARCH, 45(16), 9773–9787.
Vancouver
1.
Wen Y, Ouyang Z, Yu Y, Zhou X, Pei Y, Devreese B, et al. Mechanistic insight into how multidrug resistant Acinetobacter baumannii response regulator AdeR recognizes an intercistronic region. NUCLEIC ACIDS RESEARCH. 2017;45(16):9773–87.
MLA
Wen, Yurong, Zhenlin Ouyang, Yue Yu, et al. “Mechanistic Insight into How Multidrug Resistant Acinetobacter Baumannii Response Regulator AdeR Recognizes an Intercistronic Region.” NUCLEIC ACIDS RESEARCH 45.16 (2017): 9773–9787. Print.
@article{8539032,
  abstract     = {AdeR-AdeS is a two-component regulatory system, which controls expression of the adeABC efflux pump involved in Acinetobacter baumannii multidrug resistance. AdeR is a response regulator consisting of an N-terminal receiver domain and a C-terminal DNA-binding-domain. AdeR binds to a direct-repeat DNA in the intercistronic region between adeR and adeABC. We demonstrate a markedly high affinity binding between unphosphorylated AdeR and DNA with a dissociation constant of 20 nM. In addition, we provide a 2.75 angstrom crystal structure of AdeR DNA-binding-domain complexed with the intercistronic DNA. This structure shows that the alpha 3 and beta hairpin formed by beta 5-beta 6 interacts with the major and minor groove of the DNA, which in turn leads to the introduction of a bend. The AdeR receiver domain structure revealed a dimerization motif mediated by a gearwheel-like structure involving the D108F109-R122 motif through cation pi stack interaction. The structure of AdeR receiver domain bound with magnesium indicated a conserved Glu19Asp20-Asp63 magnesium-binding motif, and revealed that the potential phosphorylation site Asp63(OD1) forms a hydrogen bond with Lys112. We thus dissected the mechanism of how AdeR recognizes the intercistronic DNA, which leads to a diverse mode of response regulation. Unlocking the AdeRS mechanism provides ways to circumvent A. baumannii antibiotic resistance.},
  author       = {Wen, Yurong and Ouyang, Zhenlin and Yu, Yue and Zhou, Xiaorong and Pei, Yingmei and Devreese, Bart and Higgins, Paul G and Zheng, Fang},
  issn         = {0305-1048},
  journal      = {NUCLEIC ACIDS RESEARCH},
  keyword      = {2-COMPONENT SIGNAL-TRANSDUCTION,MOLECULAR-REPLACEMENT,DNA-BINDING,DOMAIN,TIGECYCLINE,ACTIVATION,SYSTEM,ADEABC,OVEREXPRESSION,EPIDEMIOLOGY},
  language     = {eng},
  number       = {16},
  pages        = {9773--9787},
  title        = {Mechanistic insight into how multidrug resistant Acinetobacter baumannii response regulator AdeR recognizes an intercistronic region},
  url          = {http://dx.doi.org/10.1093/nar/gkx624},
  volume       = {45},
  year         = {2017},
}

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