Conserved Conformational Changes in the Regulation of Mycobacterium tuberculosis MazEF-mt1

2020 ◽  
Vol 6 (7) ◽  
pp. 1783-1795
Author(s):  
Ran Chen ◽  
Jie Zhou ◽  
Runlin Sun ◽  
Chaochao Du ◽  
Wei Xie
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Conformational Changes

A user-friendly web portal for analyzing conformational changes in structures of Mycobacterium tuberculosis

2015 ◽  
Vol 21 (10) ◽  
Author(s):  
Sameer Hassan ◽  
Manonanthini Thangam ◽  
Praveen Vasudevan ◽  
G. Ramesh Kumar ◽  
Rahul Unni ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Conformational Changes ◽  
Web Portal ◽  
User Friendly

Characterization of the Mycobacterium tuberculosis H37Rv alkyl hydroperoxidase AhpC points to the importance of ionic interactions in oligomerization and activity

2001 ◽  
Vol 354 (1) ◽  
pp. 209-215 ◽  
Author(s):  
Radha CHAUHAN ◽  
Shekhar C. MANDE
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Conformational Changes ◽  
Three Dimensional ◽  
Enteric Bacteria ◽  
Enzymic Activity ◽  
Ionic Interactions ◽  
Three Dimensional Model ◽  
Mycobacterium Tuberculosis H37rv ◽  
Resistant Strains ◽  
Alkyl Hydroperoxidase

An alkyl hydroperoxidase (AhpC) has been found frequently to be overexpressed in isoniazid-resistant strains of Mycobacterium tuberculosis. These strains have an inactivated katG gene encoding a catalase peroxidase, which might render mycobacteria susceptible to the toxic peroxide radicals, thus leading to the concomitant overexpression of the AhpC. Although the overexpressed AhpC in isoniazid-resistant strains of M. tuberculosis may not directly participate in isoniazid action, AhpC might still assist M. tuberculosis in combating oxidative damage in the absence of the catalase. Here we have attempted to characterize the AhpC protein biochemically and report its functional and oligomerization properties. The alkyl hydroperoxidase of M. tuberculosis is unique in many ways compared with its well-characterized homologues from enteric bacteria. We show that AhpC is a decameric protein, composed of five identical dimers held together by ionic interactions. Dimerization of individual subunits takes place through an intersubunit disulphide linkage. The ionic interactions play a significant role in enzymic activity of the AhpC protein. The UV absorption spectrum and three-dimensional model of AhpC suggest that interesting conformational changes may take place during oxidation and reduction of the intersubunit disulphide linkage. In the absence of the partner AhpF subunit in M. tuberculosis, the mycobacterial AhpC might use small-molecule reagents, such as mycothiol, for completing its enzymic cycle.

scholarly journals The importance of the quaternary structure to represent conformational ensembles of the major Mycobacterium tuberculosis drug target

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Renata Fioravanti Tarabini ◽  
Luís Fernando Saraiva Macedo Timmers ◽  
Carlos Eduardo Sequeiros-Borja ◽  
Osmar Norberto de Souza
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Conformational Changes ◽  
Protein Function ◽  
Environmental Changes ◽  
Quaternary Structure ◽  
Single Point ◽  
Point Mutations ◽  
Conformational Ensembles ◽  
Dynamics Simulations ◽  
Coa Reductase

Abstract Flexibility is a feature intimately related to protein function, since conformational changes can be used to describe environmental changes, chemical modifications, protein-protein and protein-ligand interactions. In this study, we have investigated the influence of the quaternary structure of 2-trans-enoyl-ACP (CoA) reductase or InhA, from Mycobacterium tuberculosis, to its flexibility. We carried out classical molecular dynamics simulations using monomeric and tetrameric forms to elucidate the enzyme’s flexibility. Overall, we observed statistically significant differences between conformational ensembles of tertiary and quaternary structures. In addition, the enzyme’s binding site is the most affected region, reinforcing the importance of the quaternary structure to evaluate the binding affinity of small molecules, as well as the effect of single point mutations to InhA protein dynamics.

scholarly journals Potent Inhibitors of a Shikimate Pathway Enzyme from Mycobacterium tuberculosis

2011 ◽  
Vol 286 (18) ◽  
pp. 16197-16207 ◽  
Author(s):  
Sebastian Reichau ◽  
Wanting Jiao ◽  
Scott R. Walker ◽  
Richard D. Hutton ◽  
Edward N. Baker ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Conformational Changes ◽  
Active Site ◽  
Catalytic Mechanism ◽  
Condensation Reaction ◽  
Shikimate Pathway ◽  
Enzyme Reaction ◽  
Multidrug Resistant ◽  
Active Site Residues ◽  
Site Water

Tuberculosis remains a serious global health threat, with the emergence of multidrug-resistant strains highlighting the urgent need for novel antituberculosis drugs. The enzyme 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyzes the first step of the shikimate pathway for the biosynthesis of aromatic compounds. This pathway has been shown to be essential in Mycobacterium tuberculosis, the pathogen responsible for tuberculosis. DAH7PS catalyzes a condensation reaction between P-enolpyruvate and erythrose 4-phosphate to give 3-deoxy-d-arabino-heptulosonate 7-phosphate. The enzyme reaction mechanism is proposed to include a tetrahedral intermediate, which is formed by attack of an active site water on the central carbon of P-enolpyruvate during the course of the reaction. Molecular modeling of this intermediate into the active site reported in this study shows a configurational preference consistent with water attack from the re face of P-enolpyruvate. Based on this model, we designed and synthesized an inhibitor of DAH7PS that mimics this reaction intermediate. Both enantiomers of this intermediate mimic were potent inhibitors of M. tuberculosis DAH7PS, with inhibitory constants in the nanomolar range. The crystal structure of the DAH7PS-inhibitor complex was solved to 2.35 Å. Both the position of the inhibitor and the conformational changes of active site residues observed in this structure correspond closely to the predictions from the intermediate modeling. This structure also identifies a water molecule that is located in the appropriate position to attack the re face of P-enolpyruvate during the course of the reaction, allowing the catalytic mechanism for this enzyme to be clearly defined.

scholarly journals Three-Dimensional Structures of Apo- and Holo-l-Alanine Dehydrogenase from Mycobacterium tuberculosis Reveal Conformational Changes upon Coenzyme Binding

2008 ◽  
Vol 377 (4) ◽  
pp. 1161-1173 ◽  
Author(s):  
Daniel Ågren ◽  
Matthias Stehr ◽  
Catrine L. Berthold ◽  
Shobhna Kapoor ◽  
Wulf Oehlmann ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Conformational Changes ◽  
Three Dimensional ◽  
Coenzyme Binding ◽  
Alanine Dehydrogenase

scholarly journals GroEL2 of Mycobacterium tuberculosis Reveals the Importance of Structural Pliability in Chaperonin Function

2015 ◽  
Vol 198 (3) ◽  
pp. 486-497 ◽  
Author(s):  
Neeraja Chilukoti ◽  
C. M. Santosh Kumar ◽  
Shekhar C. Mande
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Conformational Changes ◽  
Normal Mode Analysis ◽  
Conformational Transitions ◽  
Mode Analysis ◽  
Content Type ◽  
E Coli ◽  
Allosteric Transitions

ABSTRACTIntracellular protein folding is mediated by molecular chaperones, the best studied among which are the chaperonins GroEL and GroES. Conformational changes and allosteric transitions between different metastable states are hallmarks of the chaperonin mechanism. These conformational transitions between three structural domains of GroEL are anchored at two hinges. Although hinges are known to be critical for mediating the communication between different domains of GroEL, the relative importance of hinges on GroEL oligomeric assembly, ATPase activity, conformational changes, and functional activity is not fully characterized. We have exploited the inability ofMycobacterium tuberculosisGroEL2 to functionally complement anEscherichia coligroELmutant to address the importance of hinge residues in the GroEL mechanism. Various chimeras ofM. tuberculosisGroEL2 andE. coliGroEL allowed us to understand the role of hinges and dissect the consequences of oligomerization and substrate binding capability on conformational transitions. The present study explains the concomitant conformational changes observed with GroEL hinge variants and is best supported by the normal mode analysis.IMPORTANCEConformational changes and allosteric transitions are hallmarks of the chaperonin mechanism. We have exploited the inability ofM. tuberculosisGroEL2 to functionally complement a strain ofE. coliin whichgroELexpression is repressed to address the importance of hinges. The significance of conservation at the hinge regions stands out as a prominent feature of the GroEL mechanism in binding to GroES and substrate polypeptides. The hinge residues play a significant role in the chaperonin activityin vivoandin vitro.

In Silico Analysis of S315T and S315R Mutations of Multidrug-resistant Mycobacterium tuberculosis Clinical Isolates from Karachi, Pakistan

2020 ◽  
Vol 13 (9) ◽  
Author(s):  
Muhammad Mumtaz Khan ◽  
Maria S Alves ◽  
Sadia Alam ◽  
Mohammad H Khan ◽  
Muhammad Jahangir ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistance ◽  
Conformational Changes ◽  
Gene Mutations ◽  
In Silico Analysis ◽  
Multidrug Resistant ◽  
Electrostatic Energy ◽  
Katg Gene ◽  
Resistant Strains ◽  
Binding Residues

Background: Tuberculosis is one of the most frequent and persistent global diseases causing millions of deaths every year. Pakistan lies at number 6 among the 22 most dominant countries, with multidrug resistance up to 15%. Isoniazid-resistant strains of Mycobacterium tuberculosis are gradually rising and seem to be more prevalent in developing countries. Mutations in the katG gene are considered to be responsible for the accusation of isoniazid resistance in M. tuberculosis. Objectives: The current study was designed to investigate the structural and functional associations of KatG gene mutations (S315R and S315T) and multidrug resistance in M. tuberculosis isolates from Karachi, Pakistan. Results: The present study revealed conformational changes in the structure of the KatG enzyme due to observed mutations, which led to induced alterations in isoniazid binding residues at the active site of the KatG enzyme. Furthermore, substantial changes were observed in interaction energy, ligand-receptor energy, electrostatic energy, salvation energy, and ligand-receptor conformational entropy. All these resultant modifications due to S315R and S315T mutations ultimately reduced the flexibility and stability of proteins at isoniazid-binding residues. Conclusions: This deviation in the consistency of protein texture eventually compromises the enzyme activity. It is well expected that the outcomes of the current study would provide a better understanding of the consequences of these mutations and provide a detailed insight into some previously unknown features.

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