Allostery Wiring Diagrams in the Transitions that Drive the GroEL Reaction Cycle

Tehver, Riina; Chen, Jie; Thirumalai, D.

doi:10.1016/j.jmb.2008.12.032

Cited by 82 publications

(117 citation statements)

References 52 publications

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“…GroEL is an extensively studied bacterial chaperonin that assists polypeptide chains in folding to form their native structure [84][85][86][87][88][89]. Figure 6C), whereas other † Correlation analysis performed using the alpha carbon positions of the reference atomic structure (PDB ID 1OEL) yields identical results to correlation analysis performed using FE nodes.…”

Section: Groelmentioning

confidence: 93%

Conformational dynamics of supramolecular protein assemblies

Kim

Nguyen

Bathe

2011

Journal of Structural Biology

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Supramolecular protein assemblies including molecular motors, cytoskeletal filaments, chaperones, and ribosomes play a central role in a broad array of cellular functions ranging from cell division and motility to RNA and protein synthesis and folding. Single-particle reconstructions of such assemblies have been growing rapidly in recent years, providing increasingly high resolution structural information under native conditions. While the static structure of these assemblies provides essential insight into their mechanism of biological function, their dynamical motions provide additional important information that cannot be inferred from structure alone. Here we present an unsupervised computational framework for the analysis of high molecular weight assemblies and use it to analyze the conformational dynamics of structures deposited in the Electron Microscopy Data Bank. Protein assemblies are modeled using a recently introduced coarse-grained modeling framework based on the finite element method, which is used to compute equilibrium thermal fluctuations, elastic strain energy distributions associated with specific conformational transitions, and dynamical correlations in distant molecular domains. Results are presented in detail for the ribosome-bound termination factor RF2 from Escherichia coli, the nuclear pore complex from Dictyostelium discoideum, and the chaperonin GroEL from E. coli. Elastic strain energy distributions reveal hinge-regions associated with specific conformational change pathways, and correlations in collective molecular motions reveal dynamical coupling between distant molecular domains that suggest new, as well as confirm existing, allosteric mechanisms. Results are publically available for use in further investigation and interpretation of biological function including cooperative transitions, allosteric communication, and molecular mechanics, as well as in further classification and refinement of electron microscopy based structures.

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Section: Groelmentioning

confidence: 93%

Conformational dynamics of supramolecular protein assemblies

Kim

Nguyen

Bathe

2011

Journal of Structural Biology

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“…• Central residues play a key role in the transmission of allosteric changes [65,71,95,97,101,102,127,135,[190][191][192][193]. We may use a number of centrality measures [194], including perturbation-based or game-theoretical assumptions [115,195], to find the level of importance of proteins and pathways in interactomes and signaling networks, and important amino acids in their extensions to atomic level resolution [69].…”

Section: Possible Methods To Identify Allo-network Drug Targetsmentioning

confidence: 99%

“…• Network-based analysis of perturbation propagation is a fruitful method to identify intra-protein allosteric pathways [21,44,45,[59][60][61]71,93,97,102,111,127,208]. A successful candidate for the inter-protein allosteric pathways involved in allo-network drug action disturbs network perturbations specific to a disease state of the cell at a site distant from the original drug-binding site.…”

Section: Possible Methods To Identify Allo-network Drug Targetsmentioning

confidence: 99%

“…ENMs have been used in various ways to define communication pathways. In the "structural perturbation method", the response of the network to a local structural perturbation is mapped out to define an allostery wiring diagram [101,102]. The similar "perturbation response scanning" method examines the displacement of residues when a force is applied on a selected residue [103].…”

Section: Communication Pathways From Elastic Network Modelsmentioning

confidence: 99%

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Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

Szilágyi¹,

Nussinov²,

Csermely

2013

CTMC

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Allosteric drugs are usually more specific and have fewer side effects than orthosteric drugs targeting the same protein. Here, we overview the current knowledge on allosteric signal transmission from the network point of view, and show that most intra-protein conformational changes may be dynamically transmitted across protein-protein interaction and signaling networks of the cell. Allo-network drugs influence the pharmacological target protein indirectly using specific inter-protein network pathways. We show that allo-network drugs may have a higher efficiency to change the networks of human cells than those of other organisms, and can be designed to have specific effects on cells in a diseased state. Finally, we summarize possible methods to identify allo-network drug targets and sites, which may develop to a promising new area of systems-based drug design.

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“…These studies revealed pathways of intra-molecular propagation of allosteric changes forming a network spanning the whole molecule and involving most ATP and substrate protein binding residues. Inter-modular nodes, hinges, loops and hubs were particularly important in information transmission [40][41][42][43][44].…”

Section: Protein Structure Network Of Molecular Chaperonesmentioning

confidence: 99%

System Level Mechanisms of Adaptation, Learning, Memory Formation and Evolvability: The Role of Chaperone and Other Networks

Gyurko

Sőti

Steták

et al. 2014

CPPS

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During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here, we describe first the protein structure networks of molecular chaperones, then characterize chaperone containing sub-networks of interactomes called as chaperone-networks or chaperomes. We review the role of molecular chaperones in short-term adaptation of cellular networks in response to stress, and in long-term adaptation discussing their putative functions in the regulation of evolvability. We provide a general overview of possible network mechanisms of adaptation, learning and memory formation. We propose that changes of network rigidity play a key role in learning and memory formation processes. Flexible network topology provides 'learningcompetent' state. Here, networks may have much less modular boundaries than locally rigid, highly modular networks, where the learnt information has already been consolidated in a memory formation process. Since modular boundaries are efficient filters of information, in the 'learning-competent' state information filtering may be much smaller, than after memory formation. This mechanism restricts high information transfer to the 'learning competent' state. After memory formation, modular boundary-induced segregation and information filtering protect the stored information. The flexible networks of young organisms are generally in a 'learning competent' state. On the contrary, locally rigid networks of old organisms have lost their 'learning competent' state, but store and protect their learnt information efficiently. We anticipate that the above mechanism may operate at the level of both protein-protein interaction and neuronal networks.

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Allostery Wiring Diagrams in the Transitions that Drive the GroEL Reaction Cycle

Cited by 82 publications

References 52 publications

Conformational dynamics of supramolecular protein assemblies

Conformational dynamics of supramolecular protein assemblies

Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

System Level Mechanisms of Adaptation, Learning, Memory Formation and Evolvability: The Role of Chaperone and Other Networks

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