scholarly journals Molecular and Structural Basis of Cross-Reactivity in M. tuberculosis Toxin–Antitoxin Systems

Toxins ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 481 ◽  
Author(s):  
Himani Tandon ◽  
Akhila Melarkode Vattekatte ◽  
Narayanaswamy Srinivasan ◽  
Sankaran Sandhya
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Stress Response ◽  
Structural Analysis ◽  
Chemical Nature ◽  
Structural Models ◽  
Cross Reactivity ◽  
Structural Basis ◽  
Detailed Structural Analysis ◽  
Response Network ◽  
Computational Analyses

Mycobacterium tuberculosis genome encodes over 80 toxin–antitoxin (TA) systems. While each toxin interacts with its cognate antitoxin, the abundance of TA systems presents an opportunity for potential non-cognate interactions. TA systems mediate manifold interactions to manage pathogenicity and stress response network of the cell and non-cognate interactions may play vital roles as well. To address if non-cognate and heterologous interactions are feasible and to understand the structural basis of their interactions, we have performed comprehensive computational analyses on the available 3D structures and generated structural models of paralogous M. tuberculosis VapBC and MazEF TA systems. For a majority of the TA systems, we show that non-cognate toxin–antitoxin interactions are structurally incompatible except for complexes like VapBC15 and VapBC11, which show similar interfaces and potential for cross-reactivity. For TA systems which have been experimentally shown earlier to disfavor non-cognate interactions, we demonstrate that they are structurally and stereo-chemically incompatible. For selected TA systems, our detailed structural analysis identifies specificity conferring residues. Thus, our work improves the current understanding of TA interfaces and generates a hypothesis based on congenial binding site, geometric complementarity, and chemical nature of interfaces. Overall, our work offers a structure-based explanation for non-cognate toxin-antitoxin interactions in M. tuberculosis.

scholarly journals Chemical Modification of Combusted Coal Gangue for U(VI) Adsorption: Towards a Waste Control by Waste Strategy

2021 ◽  
Vol 13 (15) ◽  
pp. 8421
Author(s):  
Yuan Gao ◽  
Jiandong Huang ◽  
Meng Li ◽  
Zhongran Dai ◽  
Rongli Jiang ◽  
...  
Keyword(s):  
Structural Analysis ◽  
High Efficiency ◽  
Low Cost ◽  
Chemical Activation ◽  
Cost Effective ◽  
Coal Gangue ◽  
Order Kinetic ◽  
Practical Applications ◽  
Detailed Structural Analysis ◽  
Alkaline Conditions

Uranium mining waste causes serious radiation-related health and environmental problems. This has encouraged efforts toward U(VI) removal with low cost and high efficiency. Typical uranium adsorbents, such as polymers, geopolymers, zeolites, and MOFs, and their associated high costs limit their practical applications. In this regard, this work found that the natural combusted coal gangue (CCG) could be a potential precursor of cheap sorbents to eliminate U(VI). The removal efficiency was modulated by chemical activation under acid and alkaline conditions, obtaining HCG (CCG activated with HCl) and KCG (CCG activated with KOH), respectively. The detailed structural analysis uncovered that those natural mineral substances, including quartz and kaolinite, were the main components in CCG and HCG. One of the key findings was that kalsilite formed in KCG under a mild synthetic condition can conspicuous enhance the affinity towards U(VI). The best equilibrium adsorption capacity with KCG was observed to be 140 mg/g under pH 6 within 120 min, following a pseudo-second-order kinetic model. To understand the improved adsorption performance, an adsorption mechanism was proposed by evaluating the pH of uranyl solutions, adsorbent dosage, as well as contact time. Combining with the structural analysis, this revealed that the uranyl adsorption process was mainly governed by chemisorption. This study gave rise to a utilization approach for CCG to obtain cost-effective adsorbents and paved a novel way towards eliminating uranium by a waste control by waste strategy.

scholarly journals Structural Basis for the C-Terminal Domain of Mycobacterium tuberculosis Ribosome Maturation Factor RimM to Bind Ribosomal Protein S19

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 597
Author(s):  
Haoran Zhang ◽  
Qiuxiang Zhou ◽  
Chenyun Guo ◽  
Liubin Feng ◽  
Huilin Wang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Ribosomal Protein ◽  
Solution Structure ◽  
Molecular Mechanisms ◽  
Structural Model ◽  
Ribosomal Subunit ◽  
Structural Basis ◽  
Hydrophobic Core ◽  
Terminal Domain ◽  
Ribosomal Protein S19

Multidrug-resistant tuberculosis (TB) is a serious threat to public health, calling for the development of new anti-TB drugs. Chaperon protein RimM, involved in the assembly of ribosomal protein S19 into 30S ribosomal subunit during ribosome maturation, is a potential drug target for TB treatment. The C-terminal domain (CTD) of RimM is primarily responsible for binding S19. However, both the CTD structure of RimM from Mycobacterium tuberculosis (MtbRimMCTD) and the molecular mechanisms underlying MtbRimMCTD binding S19 remain elusive. Here, we report the solution structure, dynamics features of MtbRimMCTD, and its interaction with S19. MtbRimMCTD has a rigid hydrophobic core comprised of a relatively conservative six-strand β-barrel, tailed with a short α-helix and interspersed with flexible loops. Using several biophysical techniques including surface plasmon resonance (SPR) affinity assays, nuclear magnetic resonance (NMR) assays, and molecular docking, we established a structural model of the MtbRimMCTD–S19 complex and indicated that the β4-β5 loop and two nonconserved key residues (D105 and H129) significantly contributed to the unique pattern of MtbRimMCTD binding S19, which might be implicated in a form of orthogonality for species-dependent RimM–S19 interaction. Our study provides the structural basis for MtbRimMCTD binding S19 and is beneficial to the further exploration of MtbRimM as a potential target for the development of new anti-TB drugs.

scholarly journals Structural Basis for P450-Mediated Oxysterol Metabolism by Mycobacterium Tuberculosis

2021 ◽  
Vol 120 (3) ◽  
pp. 119a-120a
Author(s):  
Sergey S. Bukhdruker ◽  
Tatsiana Varaksa ◽  
Irina Grabovec ◽  
Egor Marin ◽  
Anton Kavaleuski ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Structural Basis

scholarly journals Identification of fidelity-governing factors in human recombinases DMC1 and RAD51 from cryo-EM structures

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shih-Chi Luo ◽  
Hsin-Yi Yeh ◽  
Wei-Hsuan Lan ◽  
Yi-Min Wu ◽  
Cheng-Han Yang ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Structural Analysis ◽  
Md Simulation ◽  
Structural Basis ◽  
High Fidelity ◽  
Dna Dynamics ◽  
Genomic Integrity ◽  
Mismatched Dna ◽  
Dna Backbone ◽  
Loop 2

AbstractBoth high-fidelity and mismatch-tolerant recombination, catalyzed by RAD51 and DMC1 recombinases, respectively, are indispensable for genomic integrity. Here, we use cryo-EM, MD simulation and functional analysis to elucidate the structural basis for the mismatch tolerance of DMC1. Structural analysis of DMC1 presynaptic and postsynaptic complexes suggested that the lineage-specific Loop 1 Gln244 (Met243 in RAD51) may help stabilize DNA backbone, whereas Loop 2 Pro274 and Gly275 (Val273/Asp274 in RAD51) may provide an open “triplet gate” for mismatch tolerance. In support, DMC1-Q244M displayed marked increase in DNA dynamics, leading to unobservable DNA map. MD simulation showed highly dispersive mismatched DNA ensemble in RAD51 but well-converged DNA in DMC1 and RAD51-V273P/D274G. Replacing Loop 1 or Loop 2 residues in DMC1 with RAD51 counterparts enhanced DMC1 fidelity, while reciprocal mutations in RAD51 attenuated its fidelity. Our results show that three Loop 1/Loop 2 residues jointly enact contrasting fidelities of DNA recombinases.

scholarly journals Structural analysis of the human SYCE2–TEX12 complex provides molecular insights into synaptonemal complex assembly

Open Biology ◽  
2012 ◽  
Vol 2 (7) ◽  
pp. 120099 ◽  
Author(s):  
Owen R. Davies ◽  
Joseph D. Maman ◽  
Luca Pellegrini
Keyword(s):  
Structural Analysis ◽  
Synaptonemal Complex ◽  
Recurrent Miscarriage ◽  
Central Element ◽  
Biological Data ◽  
Structural Basis ◽  
Structural Framework ◽  
Chromosome Synapsis ◽  
Heterotypic Interactions ◽  
Physical Features

The successful completion of meiosis is essential for all sexually reproducing organisms. The synaptonemal complex (SC) is a large proteinaceous structure that holds together homologous chromosomes during meiosis, providing the structural framework for meiotic recombination and crossover formation. Errors in SC formation are associated with infertility, recurrent miscarriage and aneuploidy. The current lack of molecular information about the dynamic process of SC assembly severely restricts our understanding of its function in meiosis. Here, we provide the first biochemical and structural analysis of an SC protein component and propose a structural basis for its function in SC assembly. We show that human SC proteins SYCE2 and TEX12 form a highly stable, constitutive complex, and define the regions responsible for their homotypic and heterotypic interactions. Biophysical analysis reveals that the SYCE2–TEX12 complex is an equimolar hetero-octamer, formed from the association of an SYCE2 tetramer and two TEX12 dimers. Electron microscopy shows that biochemically reconstituted SYCE2–TEX12 complexes assemble spontaneously into filamentous structures that resemble the known physical features of the SC central element (CE). Our findings can be combined with existing biological data in a model of chromosome synapsis driven by growth of SYCE2–TEX12 higher-order structures within the CE of the SC.

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