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Article: Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors.

Holden, Jeffrey K / Cunningham, Christian N

2018 Volume 10, Issue 3

Abstract: The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that ... ...

Abstract	The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo.
Language	English
Publishing date	2018-03-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers10030081
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Article: Computational Site Saturation Mutagenesis of Canonical and Non-Canonical Amino Acids to Probe Protein-Peptide Interactions.

Holden, Jeffrey K / Pavlovicz, Ryan / Gobbi, Alberto / Song, Yifan / Cunningham, Christian N

Frontiers in molecular biosciences

2022 Volume 9, Page(s) 848689

Abstract: Technologies for discovering peptides as potential therapeutics have rapidly advanced in recent years with significant interest from both academic and pharmaceutical labs. These advancements in turn drive the need for new computational tools to design ... ...

Abstract	Technologies for discovering peptides as potential therapeutics have rapidly advanced in recent years with significant interest from both academic and pharmaceutical labs. These advancements in turn drive the need for new computational tools to design peptides for purposes of advancing lead molecules into the clinic. Here we report the development and application of a new automated tool, AutoRotLib, for parameterizing a diverse set of non-canonical amino acids (NCAAs), N-methyl, or peptoid residues for use with the computational design program Rosetta. In addition, we developed a protocol for designing thioether-cyclized macrocycles within Rosetta, due to their common application in mRNA display using the RaPID platform. To evaluate the utility of these new computational tools, we screened a library of canonical and NCAAs on both a linear peptide and a thioether macrocycle, allowing us to quickly identify mutations that affect peptide binding and subsequently measure our results against previously published data. We anticipate
Language	English
Publishing date	2022-04-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2022.848689
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Article ; Online: Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration.

Gerhardy, Stefan / Ultsch, Mark / Tang, Wanjian / Green, Evan / Holden, Jeffrey K / Li, Wei / Estevez, Alberto / Arthur, Chris / Tom, Irene / Rohou, Alexis / Kirchhofer, Daniel

Nature communications

2022 Volume 13, Issue 1, Page(s) 5222

Abstract: The trimeric serine protease HTRA1 is a genetic risk factor associated with geographic atrophy (GA), a currently untreatable form of age-related macular degeneration. Here, we describe the allosteric inhibition mechanism of HTRA1 by a clinical Fab ... ...

Abstract	The trimeric serine protease HTRA1 is a genetic risk factor associated with geographic atrophy (GA), a currently untreatable form of age-related macular degeneration. Here, we describe the allosteric inhibition mechanism of HTRA1 by a clinical Fab fragment, currently being evaluated for GA treatment. Using cryo-EM, X-ray crystallography and biochemical assays we identify the exposed LoopA of HTRA1 as the sole Fab epitope, which is approximately 30 Å away from the active site. The cryo-EM structure of the HTRA1:Fab complex in combination with molecular dynamics simulations revealed that Fab binding to LoopA locks HTRA1 in a non-competent conformational state, incapable of supporting catalysis. Moreover, grafting the HTRA1-LoopA epitope onto HTRA2 and HTRA3 transferred the allosteric inhibition mechanism. This suggests a conserved conformational lock mechanism across the HTRA family and a critical role of LoopA for catalysis, which was supported by the reduced activity of HTRA1-3 upon LoopA deletion or perturbation. This study reveals the long-range inhibition mechanism of the clinical Fab and identifies an essential function of the exposed LoopA for activity of HTRA family proteases.
MeSH term(s)	Crystallography, X-Ray ; Epitopes ; High-Temperature Requirement A Serine Peptidase 1/genetics ; High-Temperature Requirement A Serine Peptidase 1/metabolism ; Humans ; Immunoglobulin Fab Fragments/pharmacology ; Macular Degeneration/drug therapy ; Macular Degeneration/genetics ; Macular Degeneration/metabolism ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism
Chemical Substances	Epitopes ; Immunoglobulin Fab Fragments ; HTRA3 protein, human (EC 3.4.21.-) ; High-Temperature Requirement A Serine Peptidase 1 (EC 3.4.21.-) ; HTRA1 protein, human (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2022-09-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-32760-9
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Article ; Online: Incorporating NOE-Derived Distances in Conformer Generation of Cyclic Peptides with Distance Geometry.

Wang, Shuzhe / Krummenacher, Kajo / Landrum, Gregory A / Sellers, Benjamin D / Di Lello, Paola / Robinson, Sarah J / Martin, Bryan / Holden, Jeffrey K / Tom, Jeffrey Y K / Murthy, Anastasia C / Popovych, Nataliya / Riniker, Sereina

Journal of chemical information and modeling

2022 Volume 62, Issue 3, Page(s) 472–485

Abstract: Nuclear magnetic resonance (NMR) data from NOESY (nuclear Overhauser enhancement spectroscopy) and ROESY (rotating frame Overhauser enhancement spectroscopy) experiments can easily be combined with distance geometry (DG) based conformer generators by ... ...

Abstract	Nuclear magnetic resonance (NMR) data from NOESY (nuclear Overhauser enhancement spectroscopy) and ROESY (rotating frame Overhauser enhancement spectroscopy) experiments can easily be combined with distance geometry (DG) based conformer generators by modifying the molecular distance bounds matrix. In this work, we extend the modern DG based conformer generator ETKDG, which has been shown to reproduce experimental crystal structures from small molecules to large macrocycles well, to include NOE-derived interproton distances. In noeETKDG, the experimentally derived interproton distances are incorporated into the distance bounds matrix as loose upper (or lower) bounds to generate large conformer sets. Various subselection techniques can subsequently be applied to yield a conformer bundle that best reproduces the NOE data. The approach is benchmarked using a set of 24 (mostly) cyclic peptides for which NOE-derived distances as well as reference solution structures obtained by other software are available. With respect to other packages currently available, the advantages of noeETKDG are its speed and that no prior force-field parametrization is required, which is especially useful for peptides with unnatural amino acids. The resulting conformer bundles can be further processed with the use of structural refinement techniques to improve the modeling of the intramolecular nonbonded interactions. The noeETKDG code is released as a fully open-source software package available at www.github.com/rinikerlab/customETKDG.
MeSH term(s)	Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy/methods ; Models, Molecular ; Peptides ; Peptides, Cyclic ; Protein Conformation
Chemical Substances	Peptides ; Peptides, Cyclic
Language	English
Publishing date	2022-01-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.1c01165
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Article ; Online: Elucidating nitric oxide synthase domain interactions by molecular dynamics.

Hollingsworth, Scott A / Holden, Jeffrey K / Li, Huiying / Poulos, Thomas L

Protein science : a publication of the Protein Society

2016 Volume 25, Issue 2, Page(s) 374–382

Abstract: Nitric oxide synthase (NOS) is a multidomain enzyme that catalyzes the production of nitric oxide (NO) by oxidizing L-Arg to NO and L-citrulline. NO production requires multiple interdomain electron transfer steps between the flavin mononucleotide (FMN) ... ...

Abstract	Nitric oxide synthase (NOS) is a multidomain enzyme that catalyzes the production of nitric oxide (NO) by oxidizing L-Arg to NO and L-citrulline. NO production requires multiple interdomain electron transfer steps between the flavin mononucleotide (FMN) and heme domain. Specifically, NADPH-derived electrons are transferred to the heme-containing oxygenase domain via the flavin adenine dinucleotide (FAD) and FMN containing reductase domains. While crystal structures are available for both the reductase and oxygenase domains of NOS, to date there is no atomic level structural information on domain interactions required for the final FMN-to-heme electron transfer step. Here, we evaluate a model of this final electron transfer step for the heme-FMN-calmodulin NOS complex based on the recent biophysical studies using a 105-ns molecular dynamics trajectory. The resulting equilibrated complex structure is very stable and provides a detailed prediction of interdomain contacts required for stabilizing the NOS output state. The resulting equilibrated complex model agrees well with previous experimental work and provides a detailed working model of the final NOS electron transfer step required for NO biosynthesis.
MeSH term(s)	Calmodulin/metabolism ; Electron Transport ; Flavin Mononucleotide/metabolism ; Heme/metabolism ; Humans ; Molecular Dynamics Simulation ; NADP/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/chemistry ; Nitric Oxide Synthase Type II/metabolism ; Oxidation-Reduction ; Protein Interaction Domains and Motifs
Chemical Substances	Calmodulin ; Nitric Oxide (31C4KY9ESH) ; Heme (42VZT0U6YR) ; NADP (53-59-8) ; Flavin Mononucleotide (7N464URE7E) ; NOS2 protein, human (EC 1.14.13.39) ; Nitric Oxide Synthase Type II (EC 1.14.13.39)
Language	English
Publishing date	2016-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.2824
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Article ; Online: Identification of redox partners and development of a novel chimeric bacterial nitric oxide synthase for structure activity analyses.

Holden, Jeffrey K / Lim, Nathan / Poulos, Thomas L

The Journal of biological chemistry

2014 Volume 289, Issue 42, Page(s) 29437–29445

Abstract: Production of nitric oxide (NO) by nitric oxide synthase (NOS) requires electrons to reduce the heme iron for substrate oxidation. Both FAD and FMN flavin groups mediate the transfer of NADPH derived electrons to NOS. Unlike mammalian NOS that contain ... ...

Abstract	Production of nitric oxide (NO) by nitric oxide synthase (NOS) requires electrons to reduce the heme iron for substrate oxidation. Both FAD and FMN flavin groups mediate the transfer of NADPH derived electrons to NOS. Unlike mammalian NOS that contain both FAD and FMN binding domains within a single polypeptide chain, bacterial NOS is only composed of an oxygenase domain and must rely on separate redox partners for electron transfer and subsequent activity. Here, we report on the native redox partners for Bacillus subtilis NOS (bsNOS) and a novel chimera that promotes bsNOS activity. By identifying and characterizing native redox partners, we were also able to establish a robust enzyme assay for measuring bsNOS activity and inhibition. This assay was used to evaluate a series of established NOS inhibitors. Using the new assay for screening small molecules led to the identification of several potent inhibitors for which bsNOS-inhibitor crystal structures were determined. In addition to characterizing potent bsNOS inhibitors, substrate binding was also analyzed using isothermal titration calorimetry giving the first detailed thermodynamic analysis of substrate binding to NOS.
MeSH term(s)	Amino Acid Sequence ; Animals ; Anti-Bacterial Agents/chemistry ; Bacillus subtilis/enzymology ; Bacterial Proteins/genetics ; Calorimetry ; Cloning, Molecular ; Cytochromes c/metabolism ; Electrons ; Escherichia coli/metabolism ; Ferredoxin-NADP Reductase/genetics ; Flavodoxin/genetics ; Humans ; Imidazoles/chemistry ; Inhibitory Concentration 50 ; Microbial Sensitivity Tests ; Molecular Sequence Data ; NADH, NADPH Oxidoreductases/metabolism ; NADP/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/metabolism ; Nitrites/metabolism ; Oxidation-Reduction ; Rats
Chemical Substances	Anti-Bacterial Agents ; Bacterial Proteins ; Flavodoxin ; Imidazoles ; Nitrites ; Nitric Oxide (31C4KY9ESH) ; NADP (53-59-8) ; imidazole (7GBN705NH1) ; Cytochromes c (9007-43-6) ; Nitric Oxide Synthase (EC 1.14.13.39) ; Ferredoxin-NADP Reductase (EC 1.18.1.2) ; NADH, NADPH Oxidoreductases (EC 1.6.-) ; flavodoxin NADPH oxidoreductase (EC 1.6.-)
Language	English
Publishing date	2014-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M114.595165
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Article ; Online: Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair.

Perez-Bermejo, Juan A / Efagene, Oghene / Matern, William M / Holden, Jeffrey K / Kabir, Shaheen / Chew, Glen M / Andreoletti, Gaia / Catton, Eniola / Ennis, Craig L / Garcia, Angelica / Gerstenberg, Trevor L / Hill, Kaisle A / Jain, Aayami / Krassovsky, Kristina / Lalisan, Cassandra D / Lord, Daniel / Quejarro, B Joy / Sales-Lee, Jade / Shah, Meet /

Silva, Brian J / Skowronski, Jason / Strukov, Yuri G / Thomas, Joshua / Veraz, Michael / Vijay, Twaritha / Wallace, Kirby A / Yuan, Yue / Grogan, Jane L / Wienert, Beeke / Lahiri, Premanjali / Treusch, Sebastian / Dever, Daniel P / Soros, Vanessa B / Partridge, James R / Seim, Kristen L

Nature communications

2024 Volume 15, Issue 1, Page(s) 2625

Abstract: Homology Directed Repair (HDR) enables precise genome editing, but the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). ...

Abstract	Homology Directed Repair (HDR) enables precise genome editing, but the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we develop a functional, pooled screening platform to identify protein-based reagents that improve HDR in human hematopoietic stem and progenitor cells (HSPCs). We leverage this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target, 53BP1, identifying optimized variants that enable new intermolecular bonds and robustly increase HDR. We show that these variants specifically reduce insertion-deletion outcomes without increasing off-target editing, synergize with a DNAPK inhibitor molecule, and can be applied at manufacturing scale to increase the fraction of cells bearing repaired alleles. This screening platform can enable the discovery of future gene editing reagents that improve HDR outcomes.
MeSH term(s)	Humans ; CRISPR-Cas Systems ; Recombinational DNA Repair ; Gene Editing/methods ; DNA Repair ; DNA End-Joining Repair
Language	English
Publishing date	2024-03-23
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46816-5
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Article ; Online: Targeting Bacterial Nitric Oxide Synthase with Aminoquinoline-Based Inhibitors.

Holden, Jeffrey K / Lewis, Matthew C / Cinelli, Maris A / Abdullatif, Ziad / Pensa, Anthony V / Silverman, Richard B / Poulos, Thomas L

Biochemistry

2016 Volume 55, Issue 39, Page(s) 5587–5594

Abstract: Nitric oxide is produced in Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus by the bacterial isoform of nitric oxide synthase (NOS). Inhibition of bacterial nitric oxide synthase (bNOS) has been identified as a promising ... ...

Abstract	Nitric oxide is produced in Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus by the bacterial isoform of nitric oxide synthase (NOS). Inhibition of bacterial nitric oxide synthase (bNOS) has been identified as a promising antibacterial strategy for targeting methicillin-resistant S. aureus [Holden, J. K., et al. (2015) Chem. Biol. 22, 785-779]. One class of NOS inhibitors that demonstrates antimicrobial efficacy utilizes an aminoquinoline scaffold. Here we report on a variety of aminoquinolines that target the bacterial NOS active site, in part, by binding to a hydrophobic patch that is unique to bNOS. Through mutagenesis and crystallographic studies, our findings demonstrate that aminoquinolines are an excellent scaffold for further aiding in the development of bNOS specific inhibitors.
MeSH term(s)	Aminoquinolines/pharmacology ; Bacillus anthracis/enzymology ; Crystallography, X-Ray ; Enzyme Inhibitors/pharmacology ; Nitric Oxide Synthase/antagonists & inhibitors ; Nitric Oxide Synthase/chemistry ; Nitric Oxide Synthase/metabolism ; Staphylococcus aureus/enzymology
Chemical Substances	Aminoquinolines ; Enzyme Inhibitors ; Nitric Oxide Synthase (EC 1.14.13.39)
Language	English
Publishing date	2016-10-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.6b00786
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Article: Targeting Bacterial Nitric Oxide Synthase with Aminoquinoline-Based Inhibitors

Holden, Jeffrey K / Lewis Matthew C / Cinelli Maris A / Abdullatif Ziad / Pensa Anthony V / Silverman Richard B / Poulos Thomas L

Biochemistry. 2016 Oct. 04, v. 55, no. 39

2016

Abstract	Nitric oxide is produced in Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus by the bacterial isoform of nitric oxide synthase (NOS). Inhibition of bacterial nitric oxide synthase (bNOS) has been identified as a promising antibacterial strategy for targeting methicillin-resistant S. aureus [Holden, J. K., et al. (2015) Chem. Biol. 22, 785â779]. One class of NOS inhibitors that demonstrates antimicrobial efficacy utilizes an aminoquinoline scaffold. Here we report on a variety of aminoquinolines that target the bacterial NOS active site, in part, by binding to a hydrophobic patch that is unique to bNOS. Through mutagenesis and crystallographic studies, our findings demonstrate that aminoquinolines are an excellent scaffold for further aiding in the development of bNOS specific inhibitors.
Keywords	Bacillus anthracis ; active sites ; aminoquinolines ; anti-infective properties ; antibiotic resistance ; hydrophobicity ; methicillin ; methicillin-resistant Staphylococcus aureus ; mutagenesis ; neuronal nitric oxide synthase ; nitric oxide ; pathogens
Language	English
Dates of publication	2016-1004
Size	p. 5587-5594.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021%2Facs.biochem.6b00786
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Article ; Online: Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase.

Holden, Jeffrey K / Dejam, Dillon / Lewis, Matthew C / Huang, He / Kang, Soosung / Jing, Qing / Xue, Fengtian / Silverman, Richard B / Poulos, Thomas L

Biochemistry

2015 Volume 54, Issue 26, Page(s) 4075–4082

Abstract: Nitric oxide generated by bacterial nitric oxide synthase (NOS) increases the susceptibility of Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis to oxidative stress, including antibiotic-induced oxidative stress. Not surprisingly, NOS ...

Abstract	Nitric oxide generated by bacterial nitric oxide synthase (NOS) increases the susceptibility of Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis to oxidative stress, including antibiotic-induced oxidative stress. Not surprisingly, NOS inhibitors also improve the effectiveness of antimicrobials. Development of potent and selective bacterial NOS inhibitors is complicated by the high active site sequence and structural conservation shared with the mammalian NOS isoforms. To exploit bacterial NOS for the development of new therapeutics, recognition of alternative NOS surfaces and pharmacophores suitable for drug binding is required. Here, we report on a wide number of inhibitor-bound bacterial NOS crystal structures to identify several compounds that interact with surfaces unique to the bacterial NOS. Although binding studies indicate that these inhibitors weakly interact with the NOS active site, many of the inhibitors reported here provide a revised structural framework for the development of new antimicrobials that target bacterial NOS. In addition, mutagenesis studies reveal several key residues that unlock access to bacterial NOS surfaces that could provide the selectivity required to develop potent bacterial NOS inhibitors.
MeSH term(s)	Amino Acid Sequence ; Bacillus subtilis/chemistry ; Bacillus subtilis/enzymology ; Crystallography, X-Ray ; Drug Discovery ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Models, Molecular ; Molecular Sequence Data ; Nitric Oxide Synthase/antagonists & inhibitors ; Nitric Oxide Synthase/chemistry ; Nitric Oxide Synthase/metabolism ; Protein Conformation ; Sequence Alignment ; Staphylococcal Infections/microbiology ; Staphylococcus aureus/chemistry ; Staphylococcus aureus/enzymology
Chemical Substances	Enzyme Inhibitors ; Nitric Oxide Synthase (EC 1.14.13.39)
Language	English
Publishing date	2015-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.5b00431
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