scholarly journals Crystal Structure of the [4Fe–4S] Cluster-Containing Adenosine-5′-phosphosulfate Reductase from Mycobacterium tuberculosis

ACS Omega ◽  
2021 ◽  
Author(s):  
Patricia R. Feliciano ◽  
Kate S. Carroll ◽  
Catherine L. Drennan
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis

Crystal Structure of the Mycobacterium tuberculosis dUTPase: Insights into the Catalytic Mechanism

2004 ◽  
Vol 341 (2) ◽  
pp. 503-517 ◽  
Author(s):  
Sum Chan ◽  
Brent Segelke ◽  
Timothy Lekin ◽  
Heike Krupka ◽  
Uhn Soo Cho ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis ◽  
Catalytic Mechanism

X-ray crystal structure of Mycobacterium tuberculosis haloalkane dehalogenase Rv2579

2008 ◽  
Vol 1784 (2) ◽  
pp. 351-362 ◽  
Author(s):  
Pooja A. Mazumdar ◽  
Jordan C. Hulecki ◽  
Maia M. Cherney ◽  
Craig R. Garen ◽  
Michael N.G. James
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis ◽  
Haloalkane Dehalogenase ◽  
X Ray

scholarly journals The crystal structure of Mycobacterium tuberculosis high-temperature requirement A protein reveals an autoregulatory mechanism

2018 ◽  
Vol 74 (12) ◽  
pp. 803-809
Author(s):  
Arvind Kumar Gupta ◽  
Debashree Behera ◽  
Balasubramanian Gopal
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis ◽  
High Temperature ◽  
Catalytic Domain ◽  
Pdz Domain ◽  
Regulatory Pathways ◽  
Inactive Conformation ◽  
Temperature Requirement ◽  
Autoregulatory Mechanism

The crystal structure of Mycobacterium tuberculosis high-temperature requirement A (HtrA) protein was determined at 1.83 Å resolution. This membrane-associated protease is essential for the survival of M. tuberculosis. The crystal structure reveals that interactions between the PDZ domain and the catalytic domain in HtrA lead to an inactive conformation. This finding is consistent with its proposed role as a regulatory protease that is conditionally activated upon appropriate environmental triggers. The structure provides a basis for directed studies to evaluate the role of this essential protein and the regulatory pathways that are influenced by this protease.

The crystal structure of an essential high-temperature requirement protein HtrA1 (Rv1223) from Mycobacterium tuberculosis reveals its unique features

2018 ◽  
Vol 74 (9) ◽  
pp. 906-921 ◽  
Author(s):  
Khundrakpam Herojit Singh ◽  
Savita Yadav ◽  
Deepak Kumar ◽  
Bichitra Kumar Biswal
Keyword(s):  
Crystal Structure ◽  
Amino Acids ◽  
Mycobacterium Tuberculosis ◽  
High Temperature ◽  
Protein Quality ◽  
Pdz Domain ◽  
Survival Strategies ◽  
Dimensional Structure ◽  
Protease Domain ◽  
Temperature Requirement

High-temperature requirement A (HtrA) proteins, which are members of the heat-shock-induced serine protease family, are involved in extracytoplasmic protein quality control and bacterial survival strategies under stress conditions, and are associated with the virulence of several pathogens; they are therefore major drug targets. Mycobacterium tuberculosis possesses three putative HtrAs: HtrA1 (Rv1223), HtrA2 (Rv0983) and HtrA3 (Rv0125). Each has a cytoplasmic region, a transmembrane helix and a periplasmic region. Here, the crystal structure of the periplasmic region consisting of a protease domain (PD) and a PDZ domain from an M. tuberculosis HtrA1 mutant (mHtrA1S387A) is reported at 2.7 Å resolution. Although the mHtrA1S387A PD shows structural features similar to those of other HtrAs, its loops, particularly L3 and LA, display different conformations. Loop L3 communicates between the PDs of the trimer and the PDZ domains and undergoes a transition from an active to an inactive conformation, as reported for an equivalent HtrA (DegS). Loop LA, which is responsible for higher oligomer formation owing to its length (50 amino acids) in DegP, is very short in mHtrA1S387A (five amino acids), as in mHtrA2 (also five amino acids), and therefore lacks essential interactions for the formation of higher oligomers. Notably, a well ordered loop known as the insertion clamp in the PDZ domain interacts with the protease domain of the adjacent molecule, which possibly aids in the stabilization of a trimeric functional unit of this enzyme. The three-dimensional structure of mHtrA1S387A presented here will be useful in the design of enzyme-specific antituberculosis inhibitors.

Crystal Structure of the TetR/CamR Family Repressor Mycobacterium tuberculosis EthR Implicated in Ethionamide Resistance

2004 ◽  
Vol 340 (5) ◽  
pp. 1095-1105 ◽  
Author(s):  
Lynn G Dover ◽  
Patrick E Corsino ◽  
Ian R Daniels ◽  
Sarah L Cocklin ◽  
Vijaya Tatituri ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis

scholarly journals Synergistic Lethality of a Binary Inhibitor ofMycobacterium tuberculosisKasA

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Pradeep Kumar ◽  
Glenn C. Capodagli ◽  
Divya Awasthi ◽  
Riju Shrestha ◽  
Karishma Maharaja ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Substrate Binding ◽  
Content Type ◽  
X Ray ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Transcriptional Pattern

ABSTRACTWe report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) inMycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented thein vitroactivity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model ofM. tuberculosisinfection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB).IMPORTANCECell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors ofMycobacterium tuberculosisKasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.

scholarly journals Crystal structure of calcium dodecin (Rv0379), from Mycobacterium tuberculosis with a unique calcium-binding site

2011 ◽  
Vol 20 (5) ◽  
pp. 827-833 ◽  
Author(s):  
Arulandu Arockiasamy ◽  
Anup Aggarwal ◽  
Christos G. Savva ◽  
Andreas Holzenburg ◽  
James C. Sacchettini
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis ◽  
Binding Site ◽  
Calcium Binding ◽  
Calcium Binding Site

Crystal structure of DNA polymerase III β sliding clamp from Mycobacterium tuberculosis

2011 ◽  
Vol 405 (2) ◽  
pp. 272-277 ◽  
Author(s):  
Wen-Jun Gui ◽  
Shi-Qiang Lin ◽  
Yuan-Yuan Chen ◽  
Xian-En Zhang ◽  
Li-Jun Bi ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis ◽  
Dna Polymerase ◽  
Dna Polymerase Iii ◽  
Sliding Clamp ◽  
Polymerase Iii
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