Identification of antituberculosis agents that target ribosomal protein interactions using a yeast two-hybrid system

Lin, Yuan; Li, Yan; Zhu, Yuanjun; Zhang, Jing; Li, Yongzhen; Liu, Xiao; Jiang, Wei; Yu, Shi‐Shan; You, Xuefu; Xiao, Chunling; Hong, Bin Na; Wang, Yanchang; Jiang, Jian‐Dong; Si, Shuyi

doi:10.1073/pnas.1110271109

Cited by 29 publications

(29 citation statements)

References 34 publications

(30 reference statements)

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“…7D), a common indicator used to evaluate the relative strength of protein interactions [29,[40][41][42]. β-Galactosidase activity was activated only when the bait and pray interact with each other.…”

Section: The Coiled-coil Domain Of Arc1 Is Mainly Responsible For Itsmentioning

confidence: 99%

N-terminal domains of ARC1 are essential for interaction with the N-terminal region of Exo70A1 in transducing self-incompatibility of <italic>Brassica oleracea</italic>

Shi¹,

Gao²,

Zeng³

et al. 2016

ABBS

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Self-incompatibility (SI) is an important mating system to prevent inbreeding and promote outcrossing. ARC1 and Exo70A1 function as the downstream targets of the S-locus receptor kinase and play conservative roles in Brassica SI signaling. Based on the sequence homology, Exo70A1 is divided into four subdomains: leucine zipper (Leu are required for the interaction with Exo70A1, while the addition of ARM motif results in loss of the interaction with Exo70A1. Meanwhile, the N-terminal of Exo70A1 without any domains shows a weak interaction with ARC1, and the level of LacZ expression increases with addition of leucine zipper and reaches the maximum value with hypervariable region and SUMO modification motif, indicating that hypervariable region and SUMO modification motif of Exo70A1 172-275 is mainly responsible for the binding with ARC1, whereas pfamExo70 domain has little affinity for ARC1. Lys 181 located in the Exo70A1 hypervariable region may be the ubiquitination site mediating the interaction between ARC1 and Exo70A1. Therefore, both the leucine zipper with coiled-coil structure of ARC1 , and the hypervariable region and SUMO modification motif of Exo70A1 are the core interaction domains between ARC1 and Exo70A1. Any factors affecting these core domains would be the regulators of ARC1 mediating ubiquitin degradation in self-incompatible system.

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Section: The Coiled-coil Domain Of Arc1 Is Mainly Responsible For Itsmentioning

confidence: 99%

N-terminal domains of ARC1 are essential for interaction with the N-terminal region of Exo70A1 in transducing self-incompatibility of <italic>Brassica oleracea</italic>

Shi¹,

Gao²,

Zeng³

et al. 2016

ABBS

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“…With this system, we identified two compounds, T766 and T054, and further proved that these compounds bind to L12 to block the L12-L10 interaction and protein synthesis (11). Also, compounds T766 and T054 were confirmed to have anti-TB activity.…”

Section: Discussionmentioning

confidence: 89%

“…Using the yeast two-hybrid system, we have demonstrated the interaction between L12 and L10 from M. tuberculosis (11). In this two-hybrid system, the L12-L10 interaction induces the expression of lacZ, which encodes the enzyme ␤-galactosidase (␤-gal).…”

Section: Methodsmentioning

confidence: 99%

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The Antituberculosis Antibiotic Capreomycin Inhibits Protein Synthesis by Disrupting Interaction between Ribosomal Proteins L12 and L10

Lin

Zhu

et al. 2014

Antimicrob Agents Chemother

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cCapreomycin is a second-line drug for multiple-drug-resistant tuberculosis (TB). However, with increased use in clinics, the therapeutic efficiency of capreomycin is decreasing. To better understand TB resistance to capreomycin, we have done research to identify the molecular target of capreomycin. Mycobacterium tuberculosis ribosomal proteins L12 and L10 interact with each other and constitute the stalk of the 50S ribosomal subunit, which recruits initiation and elongation factors during translation. Hence, the L12-L10 interaction is considered to be essential for ribosomal function and protein synthesis. Here we provide evidence showing that capreomycin inhibits the L12-L10 interaction by using an established L12-L10 interaction assay. Overexpression of L12 and/or L10 in M. smegmatis, a species close to M. tuberculosis, increases the MIC of capreomycin. Moreover, both elongation factor G-dependent GTPase activity and ribosome-mediated protein synthesis are inhibited by capreomycin. When protein synthesis was blocked with thiostrepton, however, the bactericidal activity of capreomycin was restrained. All of these results suggest that capreomycin seems to inhibit TB by interrupting the L12-L10 interaction. This finding might provide novel clues for anti-TB drug discovery.

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“…The feasibility of M-PFC in a high-throughput screen platform setting was tested by performing a proof-of-concept quantitative high-throughput screen of 3600 small molecule compounds on DevR-DevR interaction. In another work, a Y2H system was used to identify small molecules that block the interaction between L12 and L10 proteins from M. tuberculosis [92]. Two compounds, T766 and T054, almost completely inhibited the b-gal activity of the strain under defined screen conditions.…”

Section: From Protein Interactions To Antimicrobial Drug Targetsmentioning

confidence: 99%

Improved understanding of pathogenesis from protein interactions inMycobacteriumtuberculosis

Cui

He²

2014

Expert Review of Proteomics

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Comprehensive mapping and analysis of protein-protein interactions provide not only systematic approaches for dissecting the infection and survival mechanisms of pathogens but also clues for discovering new antibacterial drug targets. Protein interaction data on Mycobacterium tuberculosis have rapidly accumulated over the past several years. This review summarizes the current progress of protein interaction studies on M. tuberculosis, the causative agent of tuberculosis. These efforts improve our knowledge on the stress response, signaling regulation, protein secretion and drug resistance of the bacteria. M. tuberculosis-host protein interaction studies, although still limited, have recently opened a new door for investigating the pathogenesis of the bacteria. Finally, this review discusses the importance of protein interaction data on identifying and screening new anti-tuberculosis targets and drugs, respectively.KEYWORDS: drug targets • Mycobacterium tuberculosis • pathogen-host interaction • protein-protein interaction • stress response Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is one of the most devastating human pathogens. In 2011, there were an estimated 8.7 million new cases of TB and 1.4 million people died from TB [1]. Sophisticated regulations allow M. tuberculosis to counter host-exerted harmful environments, interfere with host signaling pathways, evade immune clearance, survive and replicate in the host. Intracellular protein-protein interactions serve important functions in many complex cellular activities, such as stress response, cell signaling, transcriptional regulation, cell division, cell wall synthesis and protein secretion. In addition, interspecies pathogen-host protein interactions help the pathogen to interfere with host pathways and then evade host immune killing. Analyzing the human protein interactions involved in M. tuberculosis infection provides insights into the infection process. All these kinds of protein interaction data provide a basis for us to understand the molecular mechanisms of M. tuberculosis pathogenesis as well as clues for anti-TB drug design (FIGURE 1). In 1998, Cole et al. sequenced the complete genome of M. tuberculosis and found that this pathogen encodes approximately 4000 genes [2]. Since then, many studies have analyzed the interactions of these genes by using computational and highthroughput experimental technologies.Protein interaction data resource of M. tuberculosis Protein-protein interactions include physical interactions and functional interactions, in which physical interactions refer to the direct binding of two proteins and functional interactions mean these proteins are of functional relevance, for example, they are components of a same cell pathway. Unless specified otherwise, protein interactions in this review mean physical interactions. Obtaining protein-protein interaction data is important to elucidate the functions and mechanisms of this interaction in different cellular processes. The recent advances in the computa...

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Identification of antituberculosis agents that target ribosomal protein interactions using a yeast two-hybrid system

Cited by 29 publications

References 34 publications

N-terminal domains of ARC1 are essential for interaction with the N-terminal region of Exo70A1 in transducing self-incompatibility of <italic>Brassica oleracea</italic>

N-terminal domains of ARC1 are essential for interaction with the N-terminal region of Exo70A1 in transducing self-incompatibility of <italic>Brassica oleracea</italic>

The Antituberculosis Antibiotic Capreomycin Inhibits Protein Synthesis by Disrupting Interaction between Ribosomal Proteins L12 and L10

Improved understanding of pathogenesis from protein interactions inMycobacteriumtuberculosis

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Identification of antituberculosis agents that target ribosomal protein interactions using a yeast two-hybrid system

Cited by 29 publications

References 34 publications

N-terminal domains of ARC1 are essential for interaction with the N-terminal region of Exo70A1 in transducing self-incompatibility of &lt;italic&gt;Brassica oleracea&lt;/italic&gt;

N-terminal domains of ARC1 are essential for interaction with the N-terminal region of Exo70A1 in transducing self-incompatibility of &lt;italic&gt;Brassica oleracea&lt;/italic&gt;

The Antituberculosis Antibiotic Capreomycin Inhibits Protein Synthesis by Disrupting Interaction between Ribosomal Proteins L12 and L10

Improved understanding of pathogenesis from protein interactions inMycobacteriumtuberculosis

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N-terminal domains of ARC1 are essential for interaction with the N-terminal region of Exo70A1 in transducing self-incompatibility of <italic>Brassica oleracea</italic>

N-terminal domains of ARC1 are essential for interaction with the N-terminal region of Exo70A1 in transducing self-incompatibility of <italic>Brassica oleracea</italic>