A Chemical Perspective on Allostery

Ribeiro, André A. S. T.; Ortiz, Vanessa

doi:10.1021/acs.chemrev.5b00543

Cited by 96 publications

(80 citation statements)

References 184 publications

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“…[1][2][3][4][5][6][7] In computational studies,s ite-selective injection and subsequent tracking of energy is readily achieved. [1][2][3][4][5][6][7] In computational studies,s ite-selective injection and subsequent tracking of energy is readily achieved.…”

Section: Anisotropicvibrationalenergytransfer(vet)isexpectedtomentioning

confidence: 99%

Site‐Resolved Observation of Vibrational Energy Transfer Using a Genetically Encoded Ultrafast Heater

et al. 2019

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Allosteric information transfer in proteins has been linked to distinct vibrational energy transfer (VET) pathways in an umber of theoretical studies.E xperimental evidence for such pathways, however,i ss parse because site-selective injection of vibrational energy into aprotein, that is,localized heating,isrequired for their investigation. Here,wesolved this problem by the site-specific incorporation of the non-canonical amino acid b-(1-azulenyl)-l-alanine (AzAla) through genetic code expansion. As an exception to Kashasr ule,A zAla undergoes ultrafast internal conversion and heating after S 1 excitation while upon S 2 excitation, it serves as af luorescent label. We equipped PDZ3, ap rotein interaction domain of postsynaptic density protein 95, with this ultrafast heater at two distinct positions.W eindeed observed VET from the incorporation sites in the protein to ab ound peptide ligand on the picosecond timescale by ultrafast IR spectroscopy. This approach based on genetically encoded AzAla paves the way for detailed studies of VET and its role in aw ide range of proteins. Dr.J .Jaric Present address:H ospira Zagreb d.o.o.,aPfizer company Prudnicka cesta 60, 10291 Prigorje Brdovecko (Croatia) [ + + ]T hese authors contributed equally to this work. Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

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Section: Anisotropicvibrationalenergytransfer(vet)isexpectedtomentioning

confidence: 99%

Site‐Resolved Observation of Vibrational Energy Transfer Using a Genetically Encoded Ultrafast Heater

et al. 2019

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“…Therefore, understanding the physical basis for allostery has been a central goal of enzymology research over the past 50 years (Huang et al, 2014), resulting in several general models that describe allosteric effects. For brevity, an overview of these models is presented here, however the reader is directed to some of the many excellent reviews on the topic for further details (Cui & Karplus, 2008; Hilser, Wrabl, & Motlagh, 2012; Motlagh, Wrabl, Li, & Hilser, 2014; Ribeiro & Ortiz, in press). …”

Section: Introductionmentioning

confidence: 99%

Detecting Allosteric Networks Using Molecular Dynamics Simulation

Bowerman

Wereszczynski

2016

Methods in Enzymology

129

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Allosteric networks allow enzymes to transmit information and regulate their catalytic activities over vast distances. In principle, molecular dynamics (MD) simulations can be used to reveal the mechanisms that underlie this phenomenon; in practice, it can be difficult to discern allosteric signals from MD trajectories. Here, we describe how MD simulations can be analyzed to reveal correlated motions and allosteric networks, and provide an example of their use on the coagulation enzyme thrombin. Methods are discussed for calculating residue-pair correlations from atomic fluctuations and mutual information, which can be combined with contact information to identify allosteric networks and to dynamically cluster a system into highly correlated communities. In the case of thrombin, these methods show that binding of the antagonist hirugen significantly alters the enzyme’s correlation landscape through a series of pathways between Exosite I and the catalytic core. Results suggest that hirugen binding curtails dynamic diversity and enforces stricter venues of influence, thus reducing the accessibility of thrombin to other molecules.

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“…In three‐dimensional (3D) space, the closest distance between GDC‐0068 at the ATP‐binding site and pT308 at the A‐loop is approximately 23 Å, indicative of no direct contact between GDC‐0068 and pT308. Based on this observation, the pT308 against dephosphorylation conferred by binding of GDC‐0068 to the ATP‐binding site is through an allosteric mechanism . However, the detailed mechanism has remained elusive.…”

Section: Resultsmentioning

confidence: 99%

Microsecond molecular dynamics simulations provide insight into the ATP‐competitive inhibitor‐induced allosteric protection of Akt kinase phosphorylation

Mou

Cui

et al. 2016

Chem Biol Drug Des

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Akt is a serine/threonine protein kinase, a critical mediator of growth factor-induced survival in key cellular pathways. Allosteric signaling between protein intramolecular domains requires long-range communication mediated by hotspot residues, often triggered by ligand binding. Here, based on extensive 3 μs explicit solvent molecular dynamics (MD) simulations of Akt1 kinase domain in the unbound (apo) and ATP-competitive inhibitor, GDC-0068-bound states, we propose a molecular mechanism for allosteric regulation of Akt1 kinase phosphorylation by GDC-0068 binding to the ATP-binding site. MD simulations revealed that the apo Akt1 is flexible with two disengaged N- and C-lobes, equilibrated between the open and closed conformations. GDC-0068 occupancy of the ATP-binding site shifts the conformational equilibrium of Akt1 from the open conformation toward the closed conformation and stabilizes the closed state. This effect enables allosteric signal propagation from the GDC-0068 to the phosphorylated T308 (pT308) in the activation loop and restrains phosphatase access to pT308, thereby protecting the pT308 in the GDC-0068-bound Akt1. Importantly, functional hotspots involved in the allosteric communication from the GDC-0068 to the pT308 are identified. Our analysis of GDC-0068-induced allosteric protection of Akt kinase phosphorylation yields important new insights into the molecular mechanism of allosteric regulation of Akt kinase activity.

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A Chemical Perspective on Allostery

Cited by 96 publications

References 184 publications

Site‐Resolved Observation of Vibrational Energy Transfer Using a Genetically Encoded Ultrafast Heater

Site‐Resolved Observation of Vibrational Energy Transfer Using a Genetically Encoded Ultrafast Heater

Detecting Allosteric Networks Using Molecular Dynamics Simulation

Microsecond molecular dynamics simulations provide insight into the ATP‐competitive inhibitor‐induced allosteric protection of Akt kinase phosphorylation

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