scholarly journals Conserved Water Molecules Stabilize the Ω-Loop in Class A β-Lactamases

2008 ◽  
Vol 52 (3) ◽  
pp. 1072-1079 ◽  
Author(s):  
Fabian Bös ◽  
Jürgen Pleiss
Keyword(s):  
Phylogenetic Analysis ◽  
High Resolution ◽  
Evolutionary Relationship ◽  
Water Molecules ◽  
Protein Residues ◽  
Class A ◽  
Conserved Water Molecules ◽  
Dense Cluster ◽  
The Relationship

ABSTRACT A set of 49 high-resolution (≤2.2 Å) structures of the TEM, SHV, and CTX-M class A β-lactamase families was systematically analyzed to investigate the role of conserved water molecules in the stabilization of the Ω-loop. Overall, 13 water molecules were found to be conserved in at least 45 structures, including two water positions which were found to be conserved in all structures. Of the 13 conserved water molecules, 6 are located at the Ω-loop, forming a dense cluster with hydrogen bonds to residues at the Ω-loop as well as to the rest of the protein. This layer of conserved water molecules is packed between the Ω-loop and the rest of the protein and acts as structural glue, which could reduce the flexibility of the Ω-loop. A correlation between conserved water molecules and conserved protein residues could in general not be detected, with the exception of the conserved water molecules at the Ω-loop. Furthermore, the evolutionary relationship between the three families, derived from the number of conserved water molecules, is similar to the relationship derived from phylogenetic analysis.

scholarly journals The role of conserved water molecules in the catalytic domain of protein kinases

2009 ◽  
Vol 76 (3) ◽  
pp. 527-535 ◽  
Author(s):  
James D. R. Knight ◽  
Donald Hamelberg ◽  
J. Andrew McCammon ◽  
Rashmi Kothary
Keyword(s):  
Protein Kinases ◽  
Catalytic Domain ◽  
Water Molecules ◽  
Conserved Water Molecules

scholarly journals Electrochemistry of well-defined graphene samples: role of contaminants

2014 ◽  
Vol 172 ◽  
pp. 261-272 ◽  
Author(s):  
Hollie V. Patten ◽  
Matěj Velický ◽  
Nick Clark ◽  
Christopher A. Muryn ◽  
Ian A. Kinloch ◽  
...  
Keyword(s):  
High Resolution ◽  
Methyl Methacrylate ◽  
High Purity ◽  
Graphene Layer ◽  
Electrochemical Activity ◽  
Small Scale ◽  
Mechanical Exfoliation ◽  
The Relationship ◽  
Electrochemical Characterisation

We report the electrochemical characterisation of well-defined graphene samples, prepared by mechanical exfoliation. Mechanical exfoliation is the method of choice for high purity graphene samples, despite the inherent complexity of the approach and the small scale of the resultant flakes. However, one important, yet presently unclear area, is the role of adsorbates such as processing residue, on the properties of the graphene layer. We report high resolution microscopic and electrochemical characterisation of a variety of poly(methyl methacrylate) (PMMA) transferred graphene samples, with the explicit aim of investigating the relationship between electrochemical activity and sample purity.

scholarly journals Tunable allosteric library of caspase-3 identifies coupling between conserved water molecules and conformational selection

2016 ◽  
Vol 113 (41) ◽  
pp. E6080-E6088 ◽  
Author(s):  
Joseph J. Maciag ◽  
Sarah H. Mackenzie ◽  
Matthew B. Tucker ◽  
Joshua L. Schipper ◽  
Paul Swartz ◽  
...  
Keyword(s):  
High Resolution ◽  
Posttranslational Modifications ◽  
Caspase 3 ◽  
High Energy ◽  
Water Molecules ◽  
Active Conformation ◽  
Allosteric Site ◽  
Dimer Interface ◽  
Conformational Selection ◽  
Conserved Water Molecules

The native ensemble of caspases is described globally by a complex energy landscape where the binding of substrate selects for the active conformation, whereas targeting an allosteric site in the dimer interface selects an inactive conformation that contains disordered active-site loops. Mutations and posttranslational modifications stabilize high-energy inactive conformations, with mostly formed, but distorted, active sites. To examine the interconversion of active and inactive states in the ensemble, we used detection of related solvent positions to analyze 4,995 waters in 15 high-resolution (<2.0 Å) structures of wild-type caspase-3, resulting in 450 clusters with the most highly conserved set containing 145 water molecules. The data show that regions of the protein that contact the conserved waters also correspond to sites of posttranslational modifications, suggesting that the conserved waters are an integral part of allosteric mechanisms. To test this hypothesis, we created a library of 19 caspase-3 variants through saturation mutagenesis in a single position of the allosteric site of the dimer interface, and we show that the enzyme activity varies by more than four orders of magnitude. Altogether, our database consists of 37 high-resolution structures of caspase-3 variants, and we demonstrate that the decrease in activity correlates with a loss of conserved water molecules. The data show that the activity of caspase-3 can be fine-tuned through globally desolvating the active conformation within the native ensemble, providing a mechanism for cells to repartition the ensemble and thus fine-tune activity through conformational selection.

scholarly journals High-resolution structure of the amino acid transporter AdiC reveals insights into the role of water molecules and networks in oligomerization and substrate binding

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hüseyin Ilgü ◽  
Jean-Marc Jeckelmann ◽  
David Kalbermatter ◽  
Zöhre Ucurum ◽  
Thomas Lemmin ◽  
...  
Keyword(s):  
Amino Acid ◽  
High Resolution ◽  
Substrate Binding ◽  
Point Mutations ◽  
Md Simulations ◽  
Amino Acid Transporter ◽  
Protein Stabilization ◽  
Water Molecules ◽  
Acid Transporter

Abstract Background The L-arginine/agmatine transporter AdiC is part of the arginine-dependent extreme acid resistance system of the bacterium Escherichia coli and its pathogenic varieties such as strain E. coli O157:H7. At the present time, there is a lack of knowledge concerning the role of water molecules and networks for the structure and function of AdiC, and solute transporters in general. Results The structure of the L-arginine/agmatine transporter AdiC was determined at 1.7 Å resolution by X-ray crystallography. This high resolution allowed for the identification of numerous water molecules buried in the structure. In combination with molecular dynamics (MD) simulations, we demonstrate that water molecules play an important role for stabilizing the protein and key residues, and act as placeholders for atoms of the AdiC substrates L-arginine and agmatine. MD simulations unveiled flexibility and restrained mobility of gating residues W202 and W293, respectively. Furthermore, a water-filled cavity was identified at the dimer interface of AdiC. The two monomers formed bridging interactions through water-mediated hydrogen bonds. The accessibility and presence of water molecules in this cavity was confirmed with MD simulations. Point mutations disrupting the interfacial water network validated the importance of water molecules for dimer stabilization. Conclusions This work gives new insights into the role and importance of water molecules in the L-arginine/agmatine transporter AdiC for protein stabilization and substrate-binding site shaping and as placeholders of substrate atoms. Furthermore, and based on the observed flexibility and restrained mobility of gating residues, a mechanistic role of the gate flexibility in the transport cycle was proposed. Finally, we identified a water-filled cavity at the dimeric interface that contributes to the stability of the amino acid transporter oligomer.

scholarly journals A study on the relationship between BCG vaccination and Covid-19 prevalence: Do other confounders warrant investigation?

2020 ◽  
Author(s):  
Richard M. Mariita ◽  
Jonathan M. Musila
Keyword(s):  
Developing Countries ◽  
Phylogenetic Analysis ◽  
Potential Role ◽  
Rna Virus ◽  
Protective Role ◽  
Scientific Data ◽  
Bcg Vaccine ◽  
Bcg Vaccination ◽  
The Relationship

AbstractThe Covid-19 pandemic, which originated from Wuhan, Hubei province, China, and quickly spread to the rest of the globe is caused by SARS-CoV-2, a single-stranded RNA virus. Preliminary data suggest a relationship between the BCG vaccine and the prevalence of Covid-19. The BCG vaccine is used in the prevention of tuberculosis, a disease that is most prevalent in developing countries. To determine the potential protective role of BCG vaccination, this study investigated the occurrence of Covid-19 and the relationship between the spread of Covid-19 in countries that offer BCG vaccination and those that do not. The study also performed a phylogenetic analysis of the strains involved in the Covid-19 outbreak from the representative countries. To achieve the objectives, the study utilized publicly available data on population size, vaccination coverage, and Covid-19 cases. Phylogenetic analysis was used to determine if some SARS-CoV-2 strains were more prevalent than others. The study revealed a significant negative trend between countries that offer the BCG vaccine to the general population and the reported cases of Covid-19. The study proposes future molecular and immunological analyses to determine the potential role of BCG vaccination in protection against Covid-19. This will determine if BCG has antiviral properties, with the possibility of recommending it for widespread use if supported by scientific data.

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