Global low-frequency motions in protein allostery: CAP as a model system

Townsend, Philip D.; Rodgers, Thomas L.; Pohl, Ehmke; Wilson, Mark R.; McLeish, Tom; Cann, Martin J.

doi:10.1007/s12551-015-0163-9

Cited by 21 publications

(24 citation statements)

References 42 publications

(52 reference statements)

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“…The mechanism of allostery is still controversial. Several theoretical possibilities have been proposed (Laskowski et al 2009;Townsend et al 2015). One possibility is that a change of a local structure upon an effector molecule binding induces a change in conformation or orientation of the remote active site to fit a ligand, irrespective of the fluctuation patterns of the low-frequency normal modes.…”

Section: Discussionmentioning

confidence: 99%

“…Allostery, in which ligand binding to a protein alters an activity at a distant site, was interesting from the perspective of protein dynamics. Although Rodgers et al (2013) and Townsend et al (2015) have already discussed the allostery of CAP based on NMA, we will discuss this textbook example of allostery based on our ENM-NMA calculations.…”

Section: Illustration Of Normal Mode Analysis Protein For An Illustramentioning

confidence: 99%

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Normal mode analysis as a method to derive protein dynamics information from the Protein Data Bank

Wako

Endo

2017

Biophys Rev

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Normal mode analysis (NMA) can facilitate quick and systematic investigation of protein dynamics using data from the Protein Data Bank (PDB). We developed an elastic network model-based NMA program using dihedral angles as independent variables. Compared to the NMA programs that use Cartesian coordinates as independent variables, key attributes of the proposed program are as follows: (1) chain connectivity related to the folding pattern of a polypeptide chain is naturally embedded in the model; (2) the full-atom system is acceptable, and owing to a considerably smaller number of independent variables, the PDB data can be used without further manipulation; (3) the number of variables can be easily reduced by some of the rotatable dihedral angles; (4) the PDB data for any molecule besides proteins can be considered without coarse-graining; and (5) individual motions of constituent subunits and ligand molecules can be easily decomposed into external and internal motions to examine their mutual and intrinsic motions. Its performance is illustrated with an example of a DNA-binding allosteric protein, a catabolite activator protein. In particular, the focus is on the conformational change upon cAMP and DNA binding, and on the communication between their binding sites remotely located from each other. In this illustration, NMA creates a vivid picture of the protein dynamics at various levels of the structures, i.e., atoms, residues, secondary structures, domains, subunits, and the complete system, including DNA and cAMP. Comparative studies of the specific protein in different states, e.g., apo-and holo-conformations, and free and complexed configurations, provide useful information for studying structurally and functionally important aspects of the protein.

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Section: Discussionmentioning

confidence: 99%

Section: Illustration Of Normal Mode Analysis Protein For An Illustramentioning

confidence: 99%

Normal mode analysis as a method to derive protein dynamics information from the Protein Data Bank

Wako

Endo

2017

Biophys Rev

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“…It may be that different BLUF domains have rather different signal transduction mechanisms, but at present the evidence is strongly pointing towards the type of model proposed by Kotani almost 50 years ago (Kotani 1968), whereby vibrational changes elicit effects at a distance with no change in average structure. These vibrational properties are becoming more widely recognised as a general property of allosteric proteins (Cooper and Dryden 1984;Townsend et al 2015).…”

Section: Signalling Mechanismmentioning

confidence: 99%

Seeing the light with BLUF proteins

Park

Tame

2017

Biophys Rev

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First described about 15 years ago, BLUF (Blue Light Using Flavin) domains are light-triggered switches that control enzyme activity or gene expression in response to blue light, remaining activated for seconds or even minutes after stimulation. The conserved, ferredoxin-like fold holds a flavin chromophore that captures the light and somehow triggers downstream events. BLUF proteins are found in both prokaryotes and eukaryotes and have a variety of architectures and oligomeric forms, but the BLUF domain itself seems to have a wellpreserved structure and mechanism that have been the focus of intense study for a number of years. Crystallographic and NMR structures of BLUF domains have been solved, but the conflicting models have led to considerable debate about the atomic details of photo-activation. Advanced spectroscopic and computational methods have been used to analyse the early events after photon absorption, but these too have led to widely differing conclusions. New structural models are improving our understanding of the details of the mechanism and may lead to novel tailor-made tools for optogenetics.

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“…38–39 Most commonly ENMs are employed because long-range effects are captured well by low-frequency vibrational modes. 25, 40 …”

Section: Introductionmentioning

confidence: 99%

Decomposing Dynamical Couplings in Mutated scFv Antibody Fragments into Stabilizing and Destabilizing Effects

Ramaprasad

Uddin²,

Casas‐Finet³

et al. 2017

J. Am. Chem. Soc.

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Conformational fluctuations within scFv antibodies are characterized by a novel perturbation-response decomposition of molecular dynamics trajectories. Both perturbation and response profiles are stratified into stabilizing and destabilizing conditions. The linker between the VH and VL domains exhibits the dominant dynamical response by being coupled to nearly the entire protein, responding to both stabilizing and destabilizing perturbations. Perturbations within complementarity-determining regions (CDR) induce rich behavior in dynamic response. Among many effects, stabilizing any CDR loop in the VH domain triggers a destabilizing response in all CDR loops in the VL domain and vice versa. Destabilizing residues within the VL domain are likely to stabilize all CDR loops in the VH domain, and, when these residues are not buried the CDR loops in the VL domain are also likely to be stabilized. These effects, described by shifts in normal mode characteristics, initiate a propensity for dynamic allostery with possible functional implications in bispecific antibodies.

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Global low-frequency motions in protein allostery: CAP as a model system

Cited by 21 publications

References 42 publications

Normal mode analysis as a method to derive protein dynamics information from the Protein Data Bank

Normal mode analysis as a method to derive protein dynamics information from the Protein Data Bank

Seeing the light with BLUF proteins

Decomposing Dynamical Couplings in Mutated scFv Antibody Fragments into Stabilizing and Destabilizing Effects

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