scholarly journals Deprotonation states of the two active site water molecules regulate the binding of protein phosphatase 5 with its substrate: A molecular dynamics study

2017 ◽  
Vol 26 (10) ◽  
pp. 2010-2020 ◽  
Author(s):  
Lingyun Wang ◽  
Feng Yan
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Protein Phosphatase ◽  
Water Molecules ◽  
Protein Phosphatase 5 ◽  
Site Water

scholarly journals Relebactam Is a Potent Inhibitor of the KPC-2 β-Lactamase and Restores Imipenem Susceptibility in KPC-Producing Enterobacteriaceae

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Krisztina M. Papp-Wallace ◽  
Melissa D. Barnes ◽  
Jim Alsop ◽  
Magdalena A. Taracila ◽  
Christopher R. Bethel ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Rate Constant ◽  
Active Site ◽  
Klebsiella Oxytoca ◽  
Enterobacter Aerogenes ◽  
Clinical Isolates ◽  
Piperidine Ring ◽  
Water Molecules ◽  
Content Type ◽  
Site Water

ABSTRACT The imipenem-relebactam combination is in development as a potential treatment regimen for infections caused by Enterobacteriaceae possessing complex β-lactamase backgrounds. Relebactam is a β-lactamase inhibitor that possesses the diazabicyclooctane core, as in avibactam; however, the R1 side chain of relebactam also includes a piperidine ring, whereas that of avibactam is a carboxyamide. Here, we investigated the inactivation of the Klebsiella pneumoniae carbapenemase KPC-2, the most widespread class A carbapenemase, by relebactam and performed susceptibility testing with imipenem-relebactam using KPC-producing clinical isolates of Enterobacteriaceae . MIC measurements using agar dilution methods revealed that all 101 clinical isolates of KPC-producing Enterobacteriaceae ( K. pneumoniae , Klebsiella oxytoca , Enterobacter cloacae , Enterobacter aerogenes , Citrobacter freundii , Citrobacter koseri , and Escherichia coli ) were highly susceptible to imipenem-relebactam (MICs ≤ 2 mg/liter). Relebactam inhibited KPC-2 with a second-order onset of acylation rate constant ( k 2 / K ) value of 24,750 M −1 s −1 and demonstrated a slow off-rate constant ( k off ) of 0.0002 s −1 . Biochemical analysis using time-based mass spectrometry to map intermediates revealed that the KPC-2–relebactam acyl-enzyme complex was stable for up to 24 h. Importantly, desulfation of relebactam was not observed using mass spectrometry. Desulfation and subsequent deacylation have been observed during the reaction of KPC-2 with avibactam. Upon molecular dynamics simulations of relebactam in the KPC-2 active site, we found that the positioning of active-site water molecules is less favorable for desulfation in the KPC-2 active site than it is in the KPC-2–avibactam complex. In the acyl complexes, the water molecules are within 2.5 to 3 Å of the avibactam sulfate; however, they are more than 5 to 6 Å from the relebactam sulfate. As a result, we propose that the KPC-2–relebactam acyl complex is more stable than the KPC-2–avibactam complex. The clinical implications of this difference are not currently known.

Effects of protonation state of Asp181 and position of active site water molecules on the conformation of PTP1B

2013 ◽  
Vol 81 (5) ◽  
pp. 788-804 ◽  
Author(s):  
Ahmet Özcan ◽  
Elif Ozkirimli Olmez ◽  
Burak Alakent
Keyword(s):  
Active Site ◽  
Water Molecules ◽  
Protonation State ◽  
Site Water

Role of invariant water molecules in retaining the active site geometry of β-lactamase: a molecular dynamics simulation study

2011 ◽  
Vol 37 (15) ◽  
pp. 1234-1238 ◽  
Author(s):  
K. V. Dileep ◽  
I. Tintu ◽  
N. V. Vinod ◽  
P. P. Saliha ◽  
C. Sadasivan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Simulation Study ◽  
Active Site ◽  
Dynamics Simulation ◽  
Water Molecules

scholarly journals Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 22 ◽  
Author(s):  
Ignacio Boron ◽  
Juan Pablo Bustamante ◽  
Kelly S Davidge ◽  
Sandip Singh ◽  
Lesley AH Bowman ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Active Site ◽  
Water Molecules ◽  
Single Mutation ◽  
Truncated Hemoglobin ◽  
Kinetic Measurements ◽  
Migration Rates ◽  
Ligand Migration ◽  
Site Water ◽  
Dynamics Simulations

Mycobacterium tuberculosis, the causative agent of human tuberculosis, has two proteins belonging to the truncated hemoglobin (trHb) family. Mt-trHbN presents well-defined internal hydrophobic tunnels that allow O2 and •NO to migrate easily from the solvent to the active site, whereas Mt-trHbO possesses tunnels that are partially blocked by a few bulky residues, particularly a tryptophan at position G8. Differential ligand migration rates allow Mt-trHbN to detoxify •NO, a crucial step for pathogen survival once under attack by the immune system, much more efficiently than Mt-trHbO. In order to investigate the differences between these proteins, we performed experimental kinetic measurements, •NO decomposition, as well as molecular dynamics simulations of the wild type Mt-trHbN and two mutants, VG8F and VG8W. These mutations introduce modifications in both tunnel topologies and affect the incoming ligand capacity to displace retained water molecules at the active site. We found that a single mutation allows Mt-trHbN to acquire ligand migration rates comparable to those observed for Mt-trHbO, confirming that ligand migration is regulated by the internal tunnel architecture as well as by water molecules stabilized in the active site.

Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg2+ system: molecular dynamics and quantum calculations

2018 ◽  
Vol 24 (10) ◽  
Author(s):  
Letícia C. Assis ◽  
Alexandre A. de Castro ◽  
Ingrid G. Prandi ◽  
Daiana T. Mancini ◽  
Juliana O. S. de Giacoppo ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Protein Phosphatase ◽  
Human Protein ◽  
Quantum Calculations ◽  
Protein Phosphatase 5

The Structural Basis for Pseudoreversion of the E165D Lesion by the Secondary S96P Mutation in Triosephosphate Isomerase Depends on the Positions of Active Site Water Molecules

Biochemistry ◽  
1995 ◽  
Vol 34 (41) ◽  
pp. 13612-13621 ◽  
Author(s):  
Elizabeth A. Komives ◽  
Julie C. Lougheed ◽  
Kathleen Liu ◽  
Shigetoshi Sugio ◽  
Zhidong Zhang ◽  
...  
Keyword(s):  
Active Site ◽  
Triosephosphate Isomerase ◽  
Structural Basis ◽  
Water Molecules ◽  
Site Water

scholarly journals SET7/9 Catalytic Mutants Reveal the Role of Active Site Water Molecules in Lysine Multiple Methylation

2010 ◽  
Vol 285 (41) ◽  
pp. 31849-31858 ◽  
Author(s):  
Paul A. Del Rizzo ◽  
Jean-François Couture ◽  
Lynnette M. A. Dirk ◽  
Bethany S. Strunk ◽  
Marijo S. Roiko ◽  
...  
Keyword(s):  
Active Site ◽  
Water Molecules ◽  
Site Water

Key Role of Active-Site Water Molecules in Bacteriorhodopsin Proton-Transfer Reactions

2008 ◽  
Vol 112 (47) ◽  
pp. 14729-14741 ◽  
Author(s):  
Ana-Nicoleta Bondar ◽  
Jerome Baudry ◽  
Sándor Suhai ◽  
Stefan Fischer ◽  
Jeremy C. Smith
Keyword(s):  
Proton Transfer ◽  
Active Site ◽  
Transfer Reactions ◽  
Water Molecules ◽  
Proton Transfer Reactions ◽  
Site Water
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