The Hsp90 Inhibitor Radicicol Interacts with the ATP-Binding Pocket of Bacterial Sensor Kinase PhoQ

Guarnieri, Michael T.; Zhang, Lingdi; Shen, Jingping; Zhao, Rui

doi:10.1016/j.jmb.2008.03.036

Cited by 63 publications

(82 citation statements)

References 57 publications

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“…A PhoP-PhoQ system from S. typhimurium is a major virulence factor that is essential for this intracellular pathogen to establish infection. Inhibitors to the kinase activity of PhoQ were studied for their interactions with the protein and the inhibition mechanism by NMR and crystallography methods [57]. The structures can serve as a platform for rational design to improve the efficacy of the lead compounds.…”

Section: Therapeutic Potential Against Bacterial Pathogensmentioning

confidence: 99%

Bacterial Two-Component Systems: Structures and Signaling Mechanisms

Wang¹

2012

Protein Phosphorylation in Human Health

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Protein Phosphorylation in Human Health 440accepting chemotaxis proteins, and Phosphatases [1], hence the name. The HAMP domain connects TM2 to the dimerization and histidine phosphorylation domain (often abbreviated as DHp). A catalytic and ATP-binding (CA) domain lies at the carboxyl terminus. The combination of DHp and CA is sometimes referred to as the kinase domain. The TM helices, HAMP domains, and DHp domains are all involved in homodimerization. The sensor domain is likely to dimerize in the context of the entire protein. Sensor domains share little sequence identity, as is expected from their diverse functions of sensing various signals. However, available structures of sensor domains fall into a few common structural folds, suggesting conserved signal sensing mechanisms. The HAMP, DHp, and CA domains are common modules of HKs and have well conserved structures and sequences, especially DHp and CA, whose sequences contain several conserved motifs. There is an absolutely conserved histidine residue that is phosphorylated, and the phosphoryl group is then donated to an RR, in response to signals sensed by the sensor domain. How the sensor domain regulates the kinase activities is still unknown, due to the lack of full-length structures of the transmembrane sensor HKs. However, a large accumulation of structures of isolated domains in recent years has started to shed light on possible molecular mechanisms of the signal transduction. In this section, I will summarize these structures and discuss their conformational changes that transmit signals from the sensor domain to the kinase domain. Structures of sensor domainsSensor domains of histidine kinases are located in cytosol, in membrane, or outside of cell membrane (extracytosolic). Currently, there is little structural information of the membraneBacterial Two-Component Systems: Structures and Signaling Mechanisms 441 embedded sensor domains. The prototypical HK has an extracytosolic sensor domain that senses extracellular signals or conditions in the cell envelope. These sensor domains have highly diverse sequences. However, most of the known structures of extracytosolic sensor domains fall into three distinct structural folds, mixed , all-helical, and -sandwich. Unlike extracytosolic sensor domains, many cytosolic sensor domains can be annotated on the sequence level as PAS or GAF domains, which have related structural folds and are named from their occurrence in Period circadian, Aryl hydrocarbon receptor nuclear translocator, and Single-minded proteins (PAS) [2], or in cGMP-regulated cyclic nucleotide phosphodiesterases, Adenylate cyclases, and the bacterial transcriptional regulator FhlA (GAF) [3].

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Section: Therapeutic Potential Against Bacterial Pathogensmentioning

confidence: 99%

Bacterial Two-Component Systems: Structures and Signaling Mechanisms

Wang¹

2012

Protein Phosphorylation in Human Health

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“…The idea of using kinase inhibitors to target bacterial TCS systems has been suggested for many years, especially in light of the fact that TCS systems are not found in humans (2,25,58,62). Our genetic study reported here therefore provides a firm foundation for this strategy and further predicts that the efficacy of existing antistaphylococcal cell wall-active antibiotics might be prolonged if such kinase inhibitor compounds were to be ultimately identified and coadministered.…”

Section: Discussionmentioning

confidence: 76%

Site-Specific Mutation of Staphylococcus aureus VraS Reveals a Crucial Role for the VraR-VraS Sensor in the Emergence of Glycopeptide Resistance

Galbusera

Renzoni

Andrey

et al. 2011

Antimicrob Agents Chemother

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An initial response of Staphylococcus aureus to encounter with cell wall-active antibiotics occurs by transmembrane signaling systems that orchestrate changes in gene expression to promote survival. Histidine kinase two-component sensor-response regulators such as VraRS contribute to this response. In this study, we examined VraS membrane sensor phosphotransfer signal transduction and explored the genetic consequences of disrupting signaling by engineering a site-specific vraS chromosomal mutation. We have used in vitro autophosphorylation assay with purified VraS[64-347] lacking its transmembrane anchor region and tested site-specific kinase domain histidine mutants. We identified VraS H156 as the probable site of autophosphorylation and show phosphotransfer in vitro using purified VraR. Genetic studies show that the vraS(H156A) mutation in three strain backgrounds (ISP794, Newman, and COL) fails to generate detectable first-step reduced susceptibility teicoplanin mutants and severely reduces first-step vancomycin mutants. The emergence of low-level glycopeptide resistance in strain ISP794, derived from strain 8325 (⌬rsbU), did not require a functional B , but rsbU restoration could enhance the emergence frequency supporting a role for this alternative sigma factor in promoting glycopeptide resistance. Transcriptional analysis of vraS(H156A) strains revealed a pronounced reduction but not complete abrogation of the vraRS operon after exposure to cell wall-active antibiotics, suggesting that additional factors independent of VraS-driven phosphotransfer, or B , exist for this promoter. Collectively, our results reveal important details of the VraRS signaling system and predict that pharmacologic blockade of the VraS sensor kinase will have profound effects on blocking emergence of cell wall-active antibiotic resistance in S. aureus.

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“…To date, ten crystal structures have been reported, including four whole histidine kinase domains (CheA, Bilwes et al, 1999Bilwes et al, , 2001TM0853, Marina et al, 2005;KinB, Bick et al, 2009;ThkA, Yamada et al, 2009), one histidinecontaining phosphotransfer domain (EnvZ, Tomomori et al, 1999) and five ATP-binding catalytic domains (EnvZ, Tanaka et al, 1998;PhoQ, Marina et al, 2001, Guarnieri et al, 2008NRII, Song et al, 2004;QseC, Xie et al, 2010;PrrB, E. Nowak, S. Panjikar & P. Tucker, unpublished work). Here, we report the crystallization and preliminary X-ray diffraction analysis of the histidine kinase domain of the cytoplasmic protein HksP4 from the hyperthermophilic bacterium Aquifex aeolicus VF5.…”

Section: Introductionmentioning

confidence: 99%

Crystallization and preliminary X-ray analysis of a putative sensor histidine kinase domain: the C-terminal domain of HksP4 fromAquifex aeolicusVF5

et al. 2011

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The histidine kinase domain of the cytoplasmic protein HksP4 from the hyperthermophilic bacterium Aquifex aeolicus VF5, located in the C-terminal half of the protein, was expressed, purified and crystallized. Diffraction-quality crystals were obtained in the presence of adenosine triphosphate (ATP) or adenosine 5 0 -(,-imido)triphosphate (AMPPNP) by the sitting-drop vapour-diffusion method using PEG 3350 as the precipitant. The crystals obtained in the presence of ATP and AMPPNP diffracted X-rays to 3.1 and 2.9 Å resolution, respectively, on BL-5A at Photon Factory (Ibaraki, Japan) and were found to belong to the same space group P2 1 2 1 2 1 , with unit-cell parameters a = 80.2, b = 105.5, c = 122.0 Å and a = 81.5, b = 105.5, c = 130.9 Å , respectively. Their Matthews coefficients (V M = 2.74 and 2.51 Å 3 Da À1 , respectively) indicated that both crystals contained four protein molecules per asymmetric unit.

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The Hsp90 Inhibitor Radicicol Interacts with the ATP-Binding Pocket of Bacterial Sensor Kinase PhoQ

Cited by 63 publications

References 57 publications

Bacterial Two-Component Systems: Structures and Signaling Mechanisms

Bacterial Two-Component Systems: Structures and Signaling Mechanisms

Site-Specific Mutation of Staphylococcus aureus VraS Reveals a Crucial Role for the VraR-VraS Sensor in the Emergence of Glycopeptide Resistance

Crystallization and preliminary X-ray analysis of a putative sensor histidine kinase domain: the C-terminal domain of HksP4 fromAquifex aeolicusVF5

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