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Article ; Online: Probing ligand selectivity in pathogens.

VanSchouwen, Bryan / Melacini, Giuseppe

2023 Volume 12

Abstract: Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms? ...

Abstract	Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
MeSH term(s)	Leishmania donovani ; Ligands ; Phosphotransferases/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Purine Nucleosides/metabolism ; Trypanosoma brucei brucei
Chemical Substances	Ligands ; Phosphotransferases (EC 2.7.-) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Purine Nucleosides
Language	English
Publishing date	2023-12-21
Publishing country	England
Document type	Editorial
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.94720
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Probing ligand selectivity in pathogens

Bryan VanSchouwen / Giuseppe Melacini

eLife, Vol

2023 Volume 12

Abstract: Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms? ...

Abstract	Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Keywords	Protein kinase A ; ligand selectivity ; trypanosomatid pathogens ; T. brucei ; T. cruzi ; L. donovani ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Fractionation factors reveal hidden frustration in an ancient allosteric module.

VanSchouwen, Bryan / Della Libera, Leonardo / Melacini, Giuseppe

The Journal of chemical physics

2022 Volume 158, Issue 12, Page(s) 121101

Abstract: Protein kinase G (PKG) is an essential regulator of eukaryotic cyclic guanosine monophosphate (cGMP)-dependent intracellular signaling, controlling pathways that are often distinct from those regulated by cyclic adenosine monophosphate (cAMP). ... ...

Abstract	Protein kinase G (PKG) is an essential regulator of eukaryotic cyclic guanosine monophosphate (cGMP)-dependent intracellular signaling, controlling pathways that are often distinct from those regulated by cyclic adenosine monophosphate (cAMP). Specifically, the C-terminal cyclic-nucleotide-binding domain (CNB-B) of PKG has emerged as a critical module to control allostery and cGMP-selectivity in PKG. While key contributions to the cGMP-versus-cAMP selectivity of CNB-B were previously assessed, only limited knowledge is currently available on how cyclic nucleotide binding rewires the network of hydrogen bonds in CNB-B, and how such rewiring contributes to allostery and cGMP selectivity. To address this gap, we extend the comparative analysis of apo, cAMP- and cGMP-bound CNB-B to H/D fractionation factors (FFs), which are well-suited for assessing backbone hydrogen-bond strengths within proteins. Apo-vs-bound comparisons inform of perturbations arising from both binding and allostery, while cGMP-bound vs cAMP-bound comparisons inform of perturbations that are purely allosteric. The comparative FF analyses of the bound states revealed mixed patterns of hydrogen-bond strengthening and weakening, pointing to inherent frustration, whereby not all hydrogen bonds can be simultaneously stabilized. Interestingly, contrary to expectations, these patterns include a weakening of hydrogen bonds not only within critical recognition and allosteric elements of CNB-B, but also within elements known to undergo rigid-body movement upon cyclic nucleotide binding. These results suggest that frustration may contribute to the reversibility of allosteric conformational shifts by avoiding over-rigidification that may otherwise trap CNB-B in its active state. Considering that PKG CNB-B serves as a prototype for allosteric conformational switches, similar concepts may be applicable to allosteric domains in general.
MeSH term(s)	Nucleotides, Cyclic/metabolism ; Cyclic AMP/chemistry ; Cyclic AMP/metabolism ; Cyclic GMP/chemistry ; Cyclic GMP/metabolism ; Protein Binding ; Hydrogen
Chemical Substances	Nucleotides, Cyclic ; Cyclic AMP (E0399OZS9N) ; Cyclic GMP (H2D2X058MU) ; Hydrogen (7YNJ3PO35Z)
Language	English
Publishing date	2022-05-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	3113-6
ISSN	1089-7690 ; 0021-9606
ISSN (online)	1089-7690
ISSN	0021-9606
DOI	10.1063/5.0139510
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Article ; Online: Mutual Protein-Ligand Conformational Selection Drives cGMP vs. cAMP Selectivity in Protein Kinase G.

VanSchouwen, Bryan / Boulton, Stephen / Melacini, Giuseppe

Journal of molecular biology

2021 Volume 433, Issue 21, Page(s) 167202

Abstract: Protein kinase G (PKG) is a major receptor of cGMP, and controls signaling pathways distinct from those regulated by cAMP. However, the contributions of the two substituents that differentiate cGMP from cAMP (i.e. 6-oxo and 2- ... ...

Abstract	Protein kinase G (PKG) is a major receptor of cGMP, and controls signaling pathways distinct from those regulated by cAMP. However, the contributions of the two substituents that differentiate cGMP from cAMP (i.e. 6-oxo and 2-NH
MeSH term(s)	Binding Sites ; Cyclic AMP/chemistry ; Cyclic AMP/metabolism ; Cyclic GMP/chemistry ; Cyclic GMP/metabolism ; Cyclic GMP-Dependent Protein Kinases/chemistry ; Cyclic GMP-Dependent Protein Kinases/genetics ; Cyclic GMP-Dependent Protein Kinases/metabolism ; Gene Expression ; Humans ; Kinetics ; Ligands ; Models, Molecular ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Substrate Specificity ; Thermodynamics
Chemical Substances	Ligands ; Recombinant Proteins ; Cyclic AMP (E0399OZS9N) ; Cyclic GMP-Dependent Protein Kinases (EC 2.7.11.12) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2021-08-13
Publishing country	England
Document type	Journal Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2021.167202
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Article: Mutual Protein-Ligand Conformational Selection Drives cGMP vs. cAMP Selectivity in Protein Kinase G

VanSchouwen, Bryan / Boulton, Stephen / Melacini, Giuseppe

Journal of molecular biology. 2021 Oct. 15, v. 433, no. 21

2021

Abstract	Protein kinase G (PKG) is a major receptor of cGMP, and controls signaling pathways distinct from those regulated by cAMP. However, the contributions of the two substituents that differentiate cGMP from cAMP (i.e. 6-oxo and 2-NH₂) to the cGMP-versus-cAMP selectivity of PKG remain unclear. Here, using NMR to map how binding affinity and dynamics of the protein and ligand vary along a ligand double-substitution cycle, we show that the contributions of the two substituents to binding affinity are surprisingly non-additive. Such non-additivity stems primarily from mutual protein–ligand conformational selection, whereby not only does the ligand select for a preferred protein conformation upon binding, but also, the protein selects for a preferred ligand conformation. The 6-oxo substituent mainly controls the conformational equilibrium of the bound protein, while the 2-NH₂ substituent primarily controls the conformational equilibrium of the unbound ligand (i.e. syn versus anti). Therefore, understanding the conformational dynamics of both the protein and ligand is essential to explain the cGMP-versus-cAMP selectivity of PKG.
Keywords	cGMP-dependent protein kinase ; conformational isomerization ; ligands ; molecular biology ; protein conformation
Language	English
Dates of publication	2021-1015
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2021.167202
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Role of Dimers in the cAMP-Dependent Activation of Hyperpolarization-Activated Cyclic-Nucleotide-Modulated (HCN) Ion Channels.

VanSchouwen, Bryan / Melacini, Giuseppe

The journal of physical chemistry. B

2018 Volume 122, Issue 8, Page(s) 2177–2190

Abstract: Hyperpolarization-activated cyclic-nucleotide-modulated (HCN) ion channels control rhythmicity in neurons and cardiomyocytes. Cyclic AMP (cAMP) modulates HCN activity through the cAMP-induced formation of a tetrameric gating ring spanning the ... ...

Abstract	Hyperpolarization-activated cyclic-nucleotide-modulated (HCN) ion channels control rhythmicity in neurons and cardiomyocytes. Cyclic AMP (cAMP) modulates HCN activity through the cAMP-induced formation of a tetrameric gating ring spanning the intracellular region (IR) of HCN. Although evidence from confocal patch-clamp fluorometry indicates that the cAMP-dependent gating of HCN occurs through a dimer of dimers, the structural and dynamical basis of cAMP allostery in HCN dimers has so far remained elusive. Thus, here we examine how dimers influence IR structural dynamics, and the role that such structural dynamics play in HCN allostery. To this end, we performed molecular dynamics (MD) simulations of HCN4 IR dimers in their fully apo, fully holo, and partially cAMP-bound states, resulting in a total simulated time of 1.2 μs. Comparative analyses of these MD trajectories, as well as previous monomer and tetramer simulations utilized as benchmarks for comparison, reveal that dimers markedly sensitize the HCN IR to cAMP-modulated allostery. Our results indicate that dimerization fine-tunes the IR dynamics to enhance, relative to both monomers and tetramers, the allosteric intra- and interprotomer coupling between the cAMP-binding domain and tetramerization domain components of the IR. The resulting allosteric model provides a viable rationalization of electrophysiological data on the role of IR dimers in HCN activation.
MeSH term(s)	Cyclic AMP/chemistry ; Cyclic AMP/metabolism ; Dimerization ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/chemistry ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism ; Molecular Dynamics Simulation
Chemical Substances	Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Cyclic AMP (E0399OZS9N)
Language	English
Publishing date	2018--01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.7b10125
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Article ; Online: Divergent allostery reveals critical differences between structurally homologous regulatory domains of Plasmodium falciparum and human protein kinase G.

Byun, Jung Ah / VanSchouwen, Bryan / Huang, Jinfeng / Baryar, Ubaidullah / Melacini, Giuseppe

The Journal of biological chemistry

2022 Volume 298, Issue 3, Page(s) 101691

Abstract: Malaria is a life-threatening infectious disease primarily caused by the Plasmodium falciparum parasite. The increasing resistance to current antimalarial drugs and their side effects has led to an urgent need for novel malaria drug targets, such as the ... ...

Abstract	Malaria is a life-threatening infectious disease primarily caused by the Plasmodium falciparum parasite. The increasing resistance to current antimalarial drugs and their side effects has led to an urgent need for novel malaria drug targets, such as the P. falciparum cGMP-dependent protein kinase (pfPKG). However, PKG plays an essential regulatory role also in the human host. Human cGMP-dependent protein kinase (hPKG) and pfPKG are controlled by structurally homologous cGMP-binding domains (CBDs). Here, we show that despite the structural similarities between the essential CBDs in pfPKG and hPKG, their respective allosteric networks differ significantly. Through comparative analyses of chemical shift covariance analyses, molecular dynamics simulations, and backbone internal dynamics measurements, we found that conserved allosteric elements within the essential CBDs are wired differently in pfPKG and hPKG to implement cGMP-dependent kinase activation. Such pfPKG versus hPKG rewiring of allosteric networks was unexpected because of the structural similarity between the two essential CBDs. Yet, such finding provides crucial information on which elements to target for selective inhibition of pfPKG versus hPKG, which may potentially reduce undesired side effects in malaria treatments.
MeSH term(s)	Allosteric Regulation ; Cyclic GMP-Dependent Protein Kinases/chemistry ; Cyclic GMP-Dependent Protein Kinases/metabolism ; Humans ; Malaria, Falciparum/enzymology ; Malaria, Falciparum/parasitology ; Molecular Dynamics Simulation ; Plasmodium falciparum/enzymology ; Plasmodium falciparum/metabolism ; Protozoan Proteins/metabolism
Chemical Substances	Protozoan Proteins ; Cyclic GMP-Dependent Protein Kinases (EC 2.7.11.12)
Language	English
Publishing date	2022-02-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2022.101691
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Article ; Online: Identification of core allosteric sites through temperature- and nucleus-invariant chemical shift covariance.

Mohamed, Hebatallah / Baryar, Ubaidullah / Bashiri, Amir / Selvaratnam, Rajeevan / VanSchouwen, Bryan / Melacini, Giuseppe

Biophysical journal

2022 Volume 121, Issue 11, Page(s) 2035–2045

Abstract: Allosteric regulation is essential to control biological function. In addition, allosteric sites offer a promising venue for selective drug targeting. However, accurate mapping of allosteric sites remains challenging since allostery relies on often ... ...

Abstract	Allosteric regulation is essential to control biological function. In addition, allosteric sites offer a promising venue for selective drug targeting. However, accurate mapping of allosteric sites remains challenging since allostery relies on often subtle, yet functionally relevant, structural and dynamical changes. A viable approach proposed to overcome such challenge is chemical shift covariance analysis (CHESCA). Although CHESCA offers an exhaustive map of allosteric networks, it is critical to define the core allosteric sites to be prioritized in subsequent functional studies or in the design of allosteric drugs. Here, we propose two new CHESCA-based methodologies, called temperature CHESCA (T-CHESCA) and CLASS-CHESCA, aimed at narrowing down allosteric maps to the core allosteric residues. Both T- and CLASS-CHESCAs rely on the invariance of core inter-residue correlations to changes in the chemical shifts of the active and inactive conformations interconverting in fast exchange. In T-CHESCA the chemical shifts of such states are modulated through temperature changes, while in CLASS-CHESCA through variations in the spin-active nuclei involved in pairwise correlations. T- and CLASS-CHESCAs, as well as complete-linkage CHESCA, were applied to the cAMP-binding domain of the exchange protein directly activated by cAMP (EPAC), which serves as a prototypical allosteric switch. Residues consistently identified by the three CHESCA methods were found in previously identified EPAC allosteric core sites. Hence, T-, CLASS-, and CL-CHESCA provide a toolset to establish allosteric site hierarchy and triage allosteric sites to be further analyzed by mutations and functional assays. Furthermore, the core allosteric networks selectively revealed through T- and CLASS-CHESCA are expected to facilitate the mechanistic understanding of disease-related mutations and the design of selective allosteric modulators.
MeSH term(s)	Allosteric Regulation ; Allosteric Site ; Guanine Nucleotide Exchange Factors/metabolism ; Molecular Conformation ; Temperature
Chemical Substances	Guanine Nucleotide Exchange Factors
Language	English
Publishing date	2022-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2022.05.004
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Article ; Online: Non-Canonical Allostery in Cyclic Nucleotide Dependent Kinases.

Khamina, Mariia / Martinez Pomier, Karla / Akimoto, Madoka / VanSchouwen, Bryan / Melacini, Giuseppe

Journal of molecular biology

2022 Volume 434, Issue 17, Page(s) 167584

Abstract: The cAMP- and cGMP-dependent protein kinases (PKA and PKG) are canonically activated by the corresponding cyclic nucleotides. However, both systems are also sensitive to a wide range of non-canonical allosteric effectors, such as reactive oxygen species, ...

Abstract	The cAMP- and cGMP-dependent protein kinases (PKA and PKG) are canonically activated by the corresponding cyclic nucleotides. However, both systems are also sensitive to a wide range of non-canonical allosteric effectors, such as reactive oxygen species, which induce the formation of regulatory inter- and intra-molecular disulfide bridges, and disease-related mutations (DRMs). Here, we present a combined analysis of representative non-canonical allosteric effectors for PKA and PKG, and we identify common molecular mechanisms underlying non-canonical allostery in these kinases, from shifts in dynamical regulatory equilibria to modulation of inter-protomer interactions. In addition, mutations may also drive oligomerization beyond dimerization, and possibly phase transitions, causing loss of kinase inhibitory function and amplifying the allosteric effects of DRMs. Hence non-canonical allosteric stimuli often result in constitutive kinase activation underlying either physiological control of downstream signaling pathways or pathological outcomes, from aortic aneurisms to cancer predisposition. Overall, PKA and PKG emerge as "pan-sensors" going well beyond canonical cyclic nucleotide activation, revealing their versatile roles as central signaling hubs.
MeSH term(s)	Allosteric Regulation ; Cyclic AMP-Dependent Protein Kinases/chemistry ; Cyclic AMP-Dependent Protein Kinases/genetics ; Cyclic GMP-Dependent Protein Kinases/chemistry ; Cyclic GMP-Dependent Protein Kinases/genetics ; Humans ; Mutation ; Signal Transduction
Chemical Substances	Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Cyclic GMP-Dependent Protein Kinases (EC 2.7.11.12)
Language	English
Publishing date	2022-04-12
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2022.167584
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Article ; Online: Cracking the allosteric code of NMR chemical shifts.

VanSchouwen, Bryan / Melacini, Giuseppe

Proceedings of the National Academy of Sciences of the United States of America

2016 Volume 113, Issue 34, Page(s) 9407–9409

Language	English
Publishing date	2016-08-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1611068113
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