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Book ; Online: Machine Learning in Biomolecular Simulations

Verkhivker, Gennady / Spiwok, Vojtech / Gervasio, Francesco L.

2019

Keywords	Science: general issues ; machine learning ; molecular dynamics computer simulation ; molecular modeling ; intrinsically disordered proteins ; ligand design ; collective variable ; sampling enhancement ; non-linear dimensionality reduction ; kinetics
Size	1 electronic resource (129 pages)
Publisher	Frontiers Media SA
Document type	Book ; Online
Note	English ; Open Access
HBZ-ID	HT021230492
ISBN	9782889631360 ; 2889631362
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Conformational Flexibility and Local Frustration in the Functional States of the SARS-CoV-2 Spike B.1.1.7 and B.1.351 Variants: Mutation-Induced Allosteric Modulation Mechanism of Functional Dynamics and Protein Stability.

Verkhivker, Gennady

International journal of molecular sciences

2022 Volume 23, Issue 3

Abstract: Structural and functional studies of the SARS-CoV-2 spike proteins have recently determined distinct functional states of the B.1.1.7 and B.1.351 spike variants, providing a molecular framework for understanding the mechanisms that link the effect of ... ...

Abstract	Structural and functional studies of the SARS-CoV-2 spike proteins have recently determined distinct functional states of the B.1.1.7 and B.1.351 spike variants, providing a molecular framework for understanding the mechanisms that link the effect of mutations with the enhanced virus infectivity and transmissibility. A detailed dynamic and energetic analysis of these variants was undertaken in the present work to quantify the effects of different mutations on functional conformational changes and stability of the SARS-CoV-2 spike protein. We employed the efficient and accurate coarse-grained (CG) simulations of multiple functional states of the D614G mutant, B.1.1.7 and B.1.351 spike variants to characterize conformational dynamics of the SARS-CoV-2 spike proteins and identify dynamic signatures of the functional regions that regulate transitions between the closed and open forms. By combining molecular simulations with full atomistic reconstruction of the trajectories and the ensemble-based mutational frustration analysis, we characterized how the intrinsic flexibility of specific spike regions can control functional conformational changes required for binding with the host-cell receptor. Using the residue-based mutational scanning of protein stability, we determined protein stability hotspots and identified potential energetic drivers favoring the receptor-accessible open spike states for the B.1.1.7 and B.1.351 spike variants. The results suggested that modulation of the energetic frustration at the inter-protomer interfaces can serve as a mechanism for allosteric couplings between mutational sites and the inter-protomer hinges of functional motions. The proposed mechanism of mutation-induced energetic frustration may result in greater adaptability and the emergence of multiple conformational states in the open form. This study suggested that SARS-CoV-2 B.1.1.7 and B.1.351 variants may leverage the intrinsic plasticity of functional regions in the spike protein for mutation-induced modulation of protein dynamics and allosteric regulation to control binding with the host cell receptor.
MeSH term(s)	Allosteric Regulation ; Binding Sites ; COVID-19/metabolism ; COVID-19/pathology ; Humans ; Molecular Conformation ; Molecular Dynamics Simulation ; Mutation ; Protein Binding ; Protein Stability ; SARS-CoV-2/genetics ; SARS-CoV-2/pathogenicity ; SARS-CoV-2/ultrastructure ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/ultrastructure
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-01-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23031646
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Structural and Computational Studies of the SARS-CoV-2 Spike Protein Binding Mechanisms with Nanobodies: From Structure and Dynamics to Avidity-Driven Nanobody Engineering.

Verkhivker, Gennady

International journal of molecular sciences

2022 Volume 23, Issue 6

Abstract: Nanobodies provide important advantages over traditional antibodies, including their smaller size and robust biochemical properties such as high thermal stability, high solubility, and the ability to be bioengineered into novel multivalent, multi- ... ...

Abstract	Nanobodies provide important advantages over traditional antibodies, including their smaller size and robust biochemical properties such as high thermal stability, high solubility, and the ability to be bioengineered into novel multivalent, multi-specific, and high-affinity molecules, making them a class of emerging powerful therapies against SARS-CoV-2. Recent research efforts on the design, protein engineering, and structure-functional characterization of nanobodies and their binding with SARS-CoV-2 S proteins reflected a growing realization that nanobody combinations can exploit distinct binding epitopes and leverage the intrinsic plasticity of the conformational landscape for the SARS-CoV-2 S protein to produce efficient neutralizing and mutation resistant characteristics. Structural and computational studies have also been instrumental in quantifying the structure, dynamics, and energetics of the SARS-CoV-2 spike protein binding with nanobodies. In this review, a comprehensive analysis of the current structural, biophysical, and computational biology investigations of SARS-CoV-2 S proteins and their complexes with distinct classes of nanobodies targeting different binding sites is presented. The analysis of computational studies is supplemented by an in-depth examination of mutational scanning simulations and identification of binding energy hotspots for distinct nanobody classes. The review is focused on the analysis of mechanisms underlying synergistic binding of multivalent nanobodies that can be superior to single nanobodies and conventional nanobody cocktails in combating escape mutations by effectively leveraging binding avidity and allosteric cooperativity. We discuss how structural insights and protein engineering approaches together with computational biology tools can aid in the rational design of synergistic combinations that exhibit superior binding and neutralization characteristics owing to avidity-mediated mechanisms.
MeSH term(s)	Amino Acids ; Antibody Affinity ; Binding Sites ; Epitopes/chemistry ; Epitopes/metabolism ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Multiprotein Complexes/chemistry ; Mutagenesis ; Protein Binding ; Protein Engineering ; Protein Interaction Domains and Motifs ; Single-Domain Antibodies/chemistry ; Single-Domain Antibodies/genetics ; Single-Domain Antibodies/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Amino Acids ; Epitopes ; Multiprotein Complexes ; Single-Domain Antibodies ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-03-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23062928
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Article ; Online: Allosteric Determinants of the SARS-CoV-2 Spike Protein Binding with Nanobodies: Examining Mechanisms of Mutational Escape and Sensitivity of the Omicron Variant.

Verkhivker, Gennady

International journal of molecular sciences

2022 Volume 23, Issue 4

Abstract: Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive ... ...

Abstract	Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric determinants of the SARS-CoV-2 spike protein binding with nanobodies, we also examined nanobody-induced modulation of escaping mutations and the effect of the Omicron variant on nanobody binding. The mutational scanning analysis supported the notion that E484A mutation can have a significant detrimental effect on nanobody binding and result in Omicron-induced escape from nanobody neutralization. Our findings showed that SARS-CoV-2 spike protein might exploit the plasticity of specific allosteric hotspots to generate escape mutants that alter response to binding without compromising activity. The network analysis supported these findings showing that VHH E/VHH V nanobody binding can induce long-range couplings between the cryptic binding epitope and ACE2-binding site through a broader ensemble of communication paths that is less dependent on specific mediating centers and therefore may be less sensitive to mutational perturbations of functional residues. The results suggest that binding affinity and long-range communications of the SARS-CoV-2 complexes with nanobodies can be determined by structurally stable regulatory centers and conformationally adaptable hotspots that are allosterically coupled and collectively control resilience to mutational escape.
MeSH term(s)	Allosteric Regulation ; Cryoelectron Microscopy ; Molecular Conformation ; Molecular Dynamics Simulation ; Protein Stability ; SARS-CoV-2/genetics ; Single-Domain Antibodies/chemistry ; Single-Domain Antibodies/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Single-Domain Antibodies ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-02-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23042172
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Article ; Online: Allosteric Determinants of the SARS-CoV-2 Spike Protein Binding with Nanobodies

Gennady Verkhivker

International Journal of Molecular Sciences, Vol 23, Iss 2172, p

Examining Mechanisms of Mutational Escape and Sensitivity of the Omicron Variant

2022 Volume 2172

Abstract	Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric determinants of the SARS-CoV-2 spike protein binding with nanobodies, we also examined nanobody-induced modulation of escaping mutations and the effect of the Omicron variant on nanobody binding. The mutational scanning analysis supported the notion that E484A mutation can have a significant detrimental effect on nanobody binding and result in Omicron-induced escape from nanobody neutralization. Our findings showed that SARS-CoV-2 spike protein might exploit the plasticity of specific allosteric hotspots to generate escape mutants that alter response to binding without compromising activity. The network analysis supported these findings showing that VHH E/VHH V nanobody binding can induce long-range couplings between the cryptic binding epitope and ACE2-binding site through a broader ensemble of communication paths that is less dependent on specific mediating centers and therefore may be less sensitive to mutational perturbations of functional residues. The results suggest that binding affinity and long-range communications of the SARS-CoV-2 complexes with nanobodies can be determined by structurally stable regulatory centers and conformationally adaptable hotspots that are allosterically coupled and collectively control resilience to ...
Keywords	SARS-CoV-2 spike protein ; ACE2 host receptor ; nanobodies ; molecular dynamics ; mutational sensitivity ; binding free energy ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Conformational Flexibility and Local Frustration in the Functional States of the SARS-CoV-2 Spike B.1.1.7 and B.1.351 Variants

Gennady Verkhivker

International Journal of Molecular Sciences, Vol 23, Iss 1646, p

Mutation-Induced Allosteric Modulation Mechanism of Functional Dynamics and Protein Stability

2022 Volume 1646

Abstract	Structural and functional studies of the SARS-CoV-2 spike proteins have recently determined distinct functional states of the B.1.1.7 and B.1.351 spike variants, providing a molecular framework for understanding the mechanisms that link the effect of mutations with the enhanced virus infectivity and transmissibility. A detailed dynamic and energetic analysis of these variants was undertaken in the present work to quantify the effects of different mutations on functional conformational changes and stability of the SARS-CoV-2 spike protein. We employed the efficient and accurate coarse-grained (CG) simulations of multiple functional states of the D614G mutant, B.1.1.7 and B.1.351 spike variants to characterize conformational dynamics of the SARS-CoV-2 spike proteins and identify dynamic signatures of the functional regions that regulate transitions between the closed and open forms. By combining molecular simulations with full atomistic reconstruction of the trajectories and the ensemble-based mutational frustration analysis, we characterized how the intrinsic flexibility of specific spike regions can control functional conformational changes required for binding with the host-cell receptor. Using the residue-based mutational scanning of protein stability, we determined protein stability hotspots and identified potential energetic drivers favoring the receptor-accessible open spike states for the B.1.1.7 and B.1.351 spike variants. The results suggested that modulation of the energetic frustration at the inter-protomer interfaces can serve as a mechanism for allosteric couplings between mutational sites and the inter-protomer hinges of functional motions. The proposed mechanism of mutation-induced energetic frustration may result in greater adaptability and the emergence of multiple conformational states in the open form. This study suggested that SARS-CoV-2 B.1.1.7 and B.1.351 variants may leverage the intrinsic plasticity of functional regions in the spike protein for mutation-induced modulation of protein ...
Keywords	SARS-CoV-2 spike protein ; ACE2 host receptor ; mutational variants ; conformational dynamics ; local frustration ; mutational scanning ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	612
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural and Computational Studies of the SARS-CoV-2 Spike Protein Binding Mechanisms with Nanobodies

Gennady Verkhivker

International Journal of Molecular Sciences, Vol 23, Iss 2928, p

From Structure and Dynamics to Avidity-Driven Nanobody Engineering

2022 Volume 2928

Abstract	Nanobodies provide important advantages over traditional antibodies, including their smaller size and robust biochemical properties such as high thermal stability, high solubility, and the ability to be bioengineered into novel multivalent, multi-specific, and high-affinity molecules, making them a class of emerging powerful therapies against SARS-CoV-2. Recent research efforts on the design, protein engineering, and structure-functional characterization of nanobodies and their binding with SARS-CoV-2 S proteins reflected a growing realization that nanobody combinations can exploit distinct binding epitopes and leverage the intrinsic plasticity of the conformational landscape for the SARS-CoV-2 S protein to produce efficient neutralizing and mutation resistant characteristics. Structural and computational studies have also been instrumental in quantifying the structure, dynamics, and energetics of the SARS-CoV-2 spike protein binding with nanobodies. In this review, a comprehensive analysis of the current structural, biophysical, and computational biology investigations of SARS-CoV-2 S proteins and their complexes with distinct classes of nanobodies targeting different binding sites is presented. The analysis of computational studies is supplemented by an in-depth examination of mutational scanning simulations and identification of binding energy hotspots for distinct nanobody classes. The review is focused on the analysis of mechanisms underlying synergistic binding of multivalent nanobodies that can be superior to single nanobodies and conventional nanobody cocktails in combating escape mutations by effectively leveraging binding avidity and allosteric cooperativity. We discuss how structural insights and protein engineering approaches together with computational biology tools can aid in the rational design of synergistic combinations that exhibit superior binding and neutralization characteristics owing to avidity-mediated mechanisms.
Keywords	ACE2 host receptor ; molecular dynamics ; biophysical methods ; mutational scanning ; binding energy hotspots ; allosteric interactions ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Conformational Dynamics and Mechanisms of Client Protein Integration into the Hsp90 Chaperone Controlled by Allosteric Interactions of Regulatory Switches: Perturbation-Based Network Approach for Mutational Profiling of the Hsp90 Binding and Allostery.

Verkhivker, Gennady M

The journal of physical chemistry. B

2022

Abstract: Understanding the allosteric mechanisms of the Hsp90 chaperone interactions with cochaperones and client protein clientele is fundamental to dissect activation and regulation of many proteins. In this work, atomistic simulations are combined with ... ...

Abstract	Understanding the allosteric mechanisms of the Hsp90 chaperone interactions with cochaperones and client protein clientele is fundamental to dissect activation and regulation of many proteins. In this work, atomistic simulations are combined with perturbation-based approaches and dynamic network modeling for a comparative mutational profiling of the Hsp90 binding and allosteric interaction networks in the three Hsp90 maturation complexes with FKBP51 and P23 cochaperones and the glucocorticoid receptor (GR) client. The conformational dynamics signatures of the Hsp90 complexes and dynamics fluctuation analysis revealed how the intrinsic plasticity of the Hsp90 dimer can be modulated by cochaperones and client proteins to stabilize the closed dimer state required at the maturation stage of the ATPase cycle. In silico deep mutational scanning of the protein residues characterized the hot spots of protein stability and binding affinity in the Hsp90 complexes, showing that binding hot spots may often coincide with the regulatory centers that modulate dynamic allostery in the Hsp90 dimer. We introduce a perturbation-based network approach for mutational scanning of allosteric residue potentials and characterize allosteric switch clusters that control mechanism of cochaperone-dependent client recognition and remodeling by the Hsp90 chaperone. The results revealed a conserved network of allosteric switches in the Hsp90 complexes that allow cochaperones and GR protein to become integrated into the Hsp90 system by anchoring to the conformational switch points in the functional Hsp90 regions. This study suggests that the Hsp90 binding and allostery may operate under a regulatory mechanism in which activation or repression of the Hsp90 activity can be pre-encoded in the allosterically regulated Hsp90 dimer motions. By binding directly to the conformational switch centers on the Hsp90, cochaperones and interacting proteins can efficiently modulate the allosteric interactions and long-range communications required for client remodeling and activation.
Language	English
Publishing date	2022-07-19
Publishing country	United States
Document type	Journal Article
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.2c03464
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Article ; Online: Exploring Mechanisms of Allosteric Regulation and Communication Switching in the Multiprotein Regulatory Complexes of the Hsp90 Chaperone with Cochaperones and Client Proteins: Atomistic Insights from Integrative Biophysical Modeling and Network Analysis of Conformational Landscapes.

Verkhivker, Gennady M

Journal of molecular biology

2022 Volume 434, Issue 17, Page(s) 167506

Abstract: Understanding molecular principles underlying Hsp90 chaperone functions and modulation of client activity is fundamental to dissect activation mechanisms of many proteins. In this work, we performed a computational investigation of the Hsp90-Hsp70-Hop-CR ...

Abstract	Understanding molecular principles underlying Hsp90 chaperone functions and modulation of client activity is fundamental to dissect activation mechanisms of many proteins. In this work, we performed a computational investigation of the Hsp90-Hsp70-Hop-CR client complex to examine allosteric regulatory mechanisms underlying dynamic chaperone interactions and principles of chaperone-dependent client recognition and remodeling. Conformational dynamics analysis using high-resolution coarse-grained simulations and ensemble-based local frustration analysis suggest that the Hsp90 chaperone could recognize and recruit the GR client by invoking reciprocal dynamic exchanges near the intermolecular interfaces with the client. Using mutational scanning of the intermolecular residues in the Hsp90-Hsp70-Hop-GR complex, we identified binding energy hotspots in the regulatory complex. Perturbation-based network analysis and dynamic fluctuations-based modeling of allosteric residue potentials are employed for a detailed analysis of allosteric interaction networks and identification of conformational communication switches. We found that allosteric interactions between the Hsp90, the client-bound Hsp70 and Hop cochaperone can define two allosteric residue clusters that control client recruitment in which the intrinsic Hsp70 allostery is exploited to mediate integration of the Hsp70-bound client into the Hsp90 chaperone system. The results suggest a model of dynamics-driven allostery that enables efficient client recruitment and loading through allosteric couplings between intermolecular interfaces and communication switch centers. This study showed that the Hsp90 interactions with client proteins may operate under dynamic-based allostery in which ensembles of preexisting conformational states and intrinsic allosteric pathways present in the Hsp90 and Hsp70 chaperones can be exploited for recognition and integration of substrate proteins.
MeSH term(s)	Allosteric Regulation ; HSP70 Heat-Shock Proteins/chemistry ; HSP70 Heat-Shock Proteins/metabolism ; HSP90 Heat-Shock Proteins/chemistry ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Molecular Chaperones/chemistry ; Molecular Chaperones/metabolism ; Molecular Dynamics Simulation ; Multiprotein Complexes/chemistry ; Multiprotein Complexes/metabolism ; Protein Binding ; Protein Conformation
Chemical Substances	HSP70 Heat-Shock Proteins ; HSP90 Heat-Shock Proteins ; Molecular Chaperones ; Multiprotein Complexes
Language	English
Publishing date	2022-02-21
Publishing country	Netherlands
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.2022.167506
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Article ; Online: Making the invisible visible: Toward structural characterization of allosteric states, interaction networks, and allosteric regulatory mechanisms in protein kinases.

Verkhivker, Gennady M

Current opinion in structural biology

2021 Volume 71, Page(s) 71–78

Abstract: Despite the established view of protein kinases as dynamic and versatile allosteric regulatory machines, our knowledge of allosteric functional states, allosteric interaction networks, and the intrinsic folding energy landscapes is surprisingly limited. ... ...

Abstract	Despite the established view of protein kinases as dynamic and versatile allosteric regulatory machines, our knowledge of allosteric functional states, allosteric interaction networks, and the intrinsic folding energy landscapes is surprisingly limited. We discuss the latest developments in structural characterization of allosteric molecular events underlying protein kinase dynamics and functions using structural, biophysical, and computational biology approaches. The recent studies highlighted progress in making the invisible aspects of protein kinase 'life' visible, including the determination of hidden allosteric states and mapping of allosteric energy landscapes, discovery of new mechanisms underlying ligand-induced modulation of allosteric activity, evolutionary adaptation of kinase allostery, and characterization of allosteric interaction networks as the intrinsic driver of kinase adaptability and signal transmission in the regulatory assemblies.
MeSH term(s)	Allosteric Regulation ; Computational Biology ; Molecular Dynamics Simulation ; Protein Conformation ; Protein Kinases/metabolism
Chemical Substances	Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2021-07-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2021.06.002
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