Mycobacterium tuberculosis DNA gyrase ATPase domain structures suggest a dissociative mechanism that explains how ATP hydrolysis is coupled to domain motion

2013 ◽  
Vol 456 (2) ◽  
pp. 263-273 ◽  
Author(s):  
Alka Agrawal ◽  
Mélanie Roué ◽  
Claus Spitzfaden ◽  
Stéphanie Petrella ◽  
Alexandra Aubry ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Crystal Structures ◽  
Main Chain ◽  
Atp Hydrolysis ◽  
Dna Gyrase ◽  
Atpase Domain ◽  
Dissociative Mechanism ◽  
Hydrolysis Mechanism ◽  
Domain Structures ◽  
Atp Analogues

Crystal structures of the ATPase domain of Mycobacterium tuberculosis DNA gyrase with two different ATP analogues suggest a dissociative ATP hydrolysis mechanism, initiated when a main-chain NH moves to protonate the bridging oxygen between the terminal phosphates of ATP.

scholarly journals Ligand-induced Conformational Shift in the N-terminal Domain of GRP94, an Hsp90 Chaperone

2004 ◽  
Vol 279 (44) ◽  
pp. 46162-46171 ◽  
Author(s):  
Robert M. Immormino ◽  
D. Eric Dollins ◽  
Paul L. Shaffer ◽  
Karen L. Soldano ◽  
Melissa A. Walker ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Crystal Structures ◽  
Conformational Change ◽  
Atp Hydrolysis ◽  
Dna Gyrase ◽  
Regulatory Domain ◽  
Conformational Switch ◽  
Terminal Ligand ◽  
Conformational Rearrangement ◽  
Hsp90 Chaperone

GRP94 is the endoplasmic reticulum paralog of cytoplasmic Hsp90. Models of Hsp90 action posit an ATP-dependent conformational switch in the N-terminal ligand regulatory domain of the chaperone. However, crystal structures of the isolated N-domain of Hsp90 in complex with a variety of ligands have yet to demonstrate such a conformational change. We have determined the structure of the N-domain of GRP94 in complex with ATP, ADP, and AMP. Compared with theN-ethylcarboxamidoadenosine and radicicol-bound forms, these structures reveal a large conformational rearrangement in the protein. The nucleotide-bound form exposes new surfaces that interact to form a biochemically plausible dimer that is reminiscent of those seen in structures of MutL and DNA gyrase. Weak ATP binding and a conformational change in response to ligand identity are distinctive mechanistic features of GRP94 and suggest a model for how GRP94 functions in the absence of co-chaperones and ATP hydrolysis.

scholarly journals Crystal Structures of Escherichia coli Topoisomerase IV ParE Subunit (24 and 43 Kilodaltons): a Single Residue Dictates Differences in Novobiocin Potency against Topoisomerase IV and DNA Gyrase

2004 ◽  
Vol 48 (5) ◽  
pp. 1856-1864 ◽  
Author(s):  
Steven Bellon ◽  
Jonathan D. Parsons ◽  
Yunyi Wei ◽  
Koto Hayakawa ◽  
Lora L. Swenson ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Crystal Structures ◽  
Atp Hydrolysis ◽  
Bacterial Genome ◽  
Catalytic Efficiency ◽  
Dna Gyrase ◽  
Substrate Affinity ◽  
Topoisomerase Iv ◽  
Terminal Fragment ◽  
Essential Function

ABSTRACT Topoisomerase IV and DNA gyrase are related bacterial type II topoisomerases that utilize the free energy from ATP hydrolysis to catalyze topological changes in the bacterial genome. The essential function of DNA gyrase is the introduction of negative DNA supercoils into the genome, whereas the essential function of topoisomerase IV is to decatenate daughter chromosomes following replication. Here, we report the crystal structures of a 43-kDa N-terminal fragment of Escherichia coli topoisomerase IV ParE subunit complexed with adenylyl-imidodiphosphate at 2.0-Å resolution and a 24-kDa N-terminal fragment of the ParE subunit complexed with novobiocin at 2.1-Å resolution. The solved ParE structures are strikingly similar to the known gyrase B (GyrB) subunit structures. We also identified single-position equivalent amino acid residues in ParE (M74) and in GyrB (I78) that, when exchanged, increased the potency of novobiocin against topoisomerase IV by nearly 20-fold (to 12 nM). The corresponding exchange in gyrase (I78 M) yielded a 20-fold decrease in the potency of novobiocin (to 1.0 μM). These data offer an explanation for the observation that novobiocin is significantly less potent against topoisomerase IV than against DNA gyrase. Additionally, the enzyme kinetic parameters were affected. In gyrase, the ATP Km increased ≈5-fold and the V max decreased ≈30%. In contrast, the topoisomerase IV ATP Km decreased by a factor of 6, and the V max increased ≈2-fold from the wild-type values. These data demonstrate that the ParE M74 and GyrB I78 side chains impart opposite effects on the enzyme's substrate affinity and catalytic efficiency.

scholarly journals Crystal structures of Mycobacterium tuberculosis S‐adenosyl‐L‐homocysteine hydrolase in ternary complex with substrate and inhibitors

2008 ◽  
Vol 17 (12) ◽  
pp. 2134-2144 ◽  
Author(s):  
Manchi C.M. Reddy ◽  
Gokulan Kuppan ◽  
Nishant D. Shetty ◽  
Joshua L. Owen ◽  
Thomas R. Ioerger ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Crystal Structures ◽  
Ternary Complex

scholarly journals Crystal structures of the transpeptidase domain of the Mycobacterium tuberculosis penicillin-binding protein PonA1 reveal potential mechanisms of antibiotic resistance

FEBS Journal ◽  
2016 ◽  
Vol 283 (12) ◽  
pp. 2206-2218 ◽  
Author(s):  
Ekaterina V. Filippova ◽  
Karen J. Kieser ◽  
Chi-Hao Luan ◽  
Zdzislaw Wawrzak ◽  
Olga Kiryukhina ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Mycobacterium Tuberculosis ◽  
Crystal Structures ◽  
Binding Protein ◽  
Penicillin Binding Protein

Vanadium complexes with thiosemicarbazones: Synthesis, characterization, crystal structures and anti-Mycobacterium tuberculosis activity

Polyhedron ◽  
2009 ◽  
Vol 28 (2) ◽  
pp. 398-406 ◽  
Author(s):  
Pedro I. da S. Maia ◽  
Fernando R. Pavan ◽  
Clarice Q.F. Leite ◽  
Sebastião S. Lemos ◽  
Gerimário F. de Sousa ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Crystal Structures ◽  
Vanadium Complexes ◽  
Tuberculosis Activity

scholarly journals Extending the Definition of the GyrB Quinolone Resistance-Determining Region in Mycobacterium tuberculosis DNA Gyrase for Assessing Fluoroquinolone Resistance in M. tuberculosis

2012 ◽  
Vol 56 (4) ◽  
pp. 1990-1996 ◽  
Author(s):  
Alix Pantel ◽  
Stéphanie Petrella ◽  
Nicolas Veziris ◽  
Florence Brossier ◽  
Sylvaine Bastian ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hot Spot ◽  
Dna Gyrase ◽  
Quinolone Resistance ◽  
Fluoroquinolone Resistance ◽  
Wild Type ◽  
Content Type ◽  
Highly Active ◽  
Definition Of

ABSTRACTFluoroquinolone (FQ) resistance is emerging inMycobacterium tuberculosis. The main mechanism of FQ resistance is amino acid substitution within the quinolone resistance-determining region (QRDR) of the GyrA subunit of DNA gyrase, the sole FQ target inM. tuberculosis. However, substitutions in GyrB whose implication in FQ resistance is unknown are increasingly being reported. The present study clarified the role of four GyrB substitutions identified inM. tuberculosisclinical strains, two located in the QRDR (D500A and N538T) and two outside the QRDR (T539P and E540V), in FQ resistance. We measured FQ MICs and also DNA gyrase inhibition by FQs in order to unequivocally clarify the role of these mutations in FQ resistance. Wild-type GyrA, wild-type GyrB, and mutant GyrB subunits produced from engineeredgyrBalleles by mutagenesis were overexpressed inEscherichia coli, purified to homogeneity, and used to reconstitute highly active gyrase complexes. MICs and DNA gyrase inhibition were determined for moxifloxacin, gatifloxacin, ofloxacin, levofloxacin, and enoxacin. All these substitutions are clearly implicated in FQ resistance, underlining the presence of a hot spot region housing most of the GyrB substitutions implicated in FQ resistance (residues NTE, 538 to 540). These findings help us to refine the definition of GyrB QRDR, which is extended to positions 500 to 540.

scholarly journals Theoretical Study on the ATP Hydrolysis Mechanism of HisP Protein, the ATP-Binding Subunit of ABC Transporter

2007 ◽  
Vol 48 (4) ◽  
pp. 735-739 ◽  
Author(s):  
Qiang Pei ◽  
Carlos A. Del Carpio ◽  
Hideyuki Tsuboi ◽  
Michihisa Koyama ◽  
Akira Endou ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Theoretical Study ◽  
Atp Hydrolysis ◽  
Atp Binding ◽  
Hydrolysis Mechanism ◽  
Binding Subunit

scholarly journals Crystal structures of the apo and ATP bound Mycobacterium tuberculosis nitrogen regulatory PII protein

2010 ◽  
Vol 19 (8) ◽  
pp. 1513-1524 ◽  
Author(s):  
Nishant D. Shetty ◽  
Manchi C. M. Reddy ◽  
Satheesh K. Palaninathan ◽  
Joshua L. Owen ◽  
James C. Sacchettini
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Crystal Structures ◽  
Pii Protein

scholarly journals Structural Asymmetry in the Closed State of Mitochondrial Hsp90 (TRAP1) Supports a Two-Step ATP Hydrolysis Mechanism

2014 ◽  
Vol 53 (2) ◽  
pp. 330-343 ◽  
Author(s):  
Laura A. Lavery ◽  
James R. Partridge ◽  
Theresa A. Ramelot ◽  
Daniel Elnatan ◽  
Michael A. Kennedy ◽  
...  
Keyword(s):  
Atp Hydrolysis ◽  
Structural Asymmetry ◽  
Hydrolysis Mechanism ◽  
Closed State

ChemInform Abstract: Design, Synthesis, and Structure-Activity Relationship Studies of ATP Analogues as DNA Gyrase Inhibitors.

ChemInform ◽  
2010 ◽  
Vol 31 (30) ◽  
pp. no-no
Author(s):  
Thomas Luebbers ◽  
Peter Angehrn ◽  
Hans Gmuender ◽  
Silvia Herzig ◽  
Josef Kulhanek
Keyword(s):  
Dna Gyrase ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Design Synthesis ◽  
Structure Activity ◽  
Atp Analogues ◽  
Gyrase Inhibitors
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