Dynamics of Cleft Closure of the GluA2 Ligand-binding Domain in the Presence of Full and Partial Agonists Revealed by Hydrogen-Deuterium Exchange

Ahmed, Ahmed H.; Ptak, Christopher; Fenwick, Michael K.; Hsieh, Ching-Lin; Weiland, Gregory A.; Oswald, Robert E.

doi:10.1074/jbc.m113.495564

Cited by 27 publications

(29 citation statements)

References 31 publications

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“…For example, mutations that disrupted an inter-lobe hydrogen bond in GluA2 decreased both agonist affinity and efficacy (Robert et al, 2005). NMR data indicated that, compared to partial agonists with high efficacies, those with low efficacies induced a less stable cleft closure of the GluA2 LBD (Ahmed et al, 2013; Maltsev et al, 2008). According to single molecule FRET experiments on the GluA2 LBD in complex with several partial agonists, the fraction of time that the LBD spent in cleft-closed conformations correlated with the extent of channel activation (Ramaswamy et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Reduced Curvature of Ligand-Binding Domain Free-Energy Surface Underlies Partial Agonism at NMDA Receptors

Dai

Zhou

2015

Structure

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NMDA receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the central nervous system. Partial agonists elicit submaximal channel activation, but crystal structures of the ligand-binding domains (LBDs) bound with partial and full agonists show little difference. To uncover the molecular mechanism for partial agonism, here we computed the free energy surfaces of the GluN1 (an obligatory subunit of NMDA receptors) LBD bound with a variety of ligands. The free energy minima are similarly positioned for full and partial agonists, but the curvatures are significantly reduced in the latter case, indicating higher probabilities for sampling conformations with a not fully closed domain cleft. The free energy surfaces for antagonists have both shifted minima and further reduced curvatures. Reduced curvature of free energy surface appears to explain well the partial agonism at NMDA receptors and may present a unique paradigm in producing graded responses for receptors in general.

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Section: Introductionmentioning

confidence: 99%

Reduced Curvature of Ligand-Binding Domain Free-Energy Surface Underlies Partial Agonism at NMDA Receptors

Dai

Zhou

2015

Structure

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“…Such a relationship between agonist-binding domain cleft closure and ion channel activation provides an elegant means of explaining the link between conformational changes at the agonist-binding site and opening of the channel pore (11). Single molecule fluorescence resonance energy transfer (smFRET) experiments as well as NMR show that, in addition to the inherent ability of a ligand to induce cleft closure, the dynamics also play an important role in dictating activation (12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Structural Dynamics of the Glycine-binding Domain of the N-Methyl-d-Aspartate Receptor

Dolino¹,

Cooper

Ramaswamy³

et al. 2015

Journal of Biological Chemistry

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Background:The agonist glycine binds to a cleft in the bilobed extracellular domain of NMDA receptors. Results: The full agonist-bound forms of the agonist-binding domain populate more of the higher efficiency closed-cleft states of the receptor. Conclusion: Cleft closure dynamics differ for the full and partial agonist-bound forms. Significance: Dynamics and the extent of cleft closure control agonist efficacy.

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“…Relatively small ligands can act as GluK2 specific partial agonists, which may arise from the weak link between D1 and D2 of the LBD of this receptor type. A very recent study (Ahmed et al 2013), using hydrogen-deuterium exchange method, supports the view of hydrogen bonding stability being important in distinguishing full and partial agnists at least in GluA2. In that study, stabilisation of the interdomain H-bonds was weaker for partial than for full agonists.…”

Section: Ihb Disruption Enables Categorisation Of Ligands As Full or mentioning

confidence: 76%

“…In addition to crystallisation, the ligand-binding induced cleft-closure has been extensively studied with several other experimental methods, such as radioligand binding ), fluorescence resonance energy transfer , electrophysiology , nuclear magnetic resonance spectroscopy (Ahmed et al 2013), and site-directed mutagenesis (Weston et al 2006). Recently, computational methods, especially MD simulations, have been utilised to improve our knowledge on the iGluR family structure and function.…”

Section: Ligand-binding Domain Structure and Activationmentioning

confidence: 99%

Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone

Ylilauri

Mattila

Nurminen

et al. 2013

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Esitetään Jyväskylän yliopiston matemaattis-luonnontieteellisen tiedekunnan suostumuksella julkisesti tarkastettavaksi yliopiston Ylistönrinteellä, salissa YAA303 tammikuun 24. päivänä 2014 kello 12.Academic dissertation to be publicly discussed, by permission of the Faculty of Mathematics and Science of the University of Jyväskylä, in Ylistönrinne, hall YAA303, on January 24, 2014 at 12 o'clock noon. Ligand-binding in a specific manner is vital to all cellular actions and can have a major effect on the activity and conformation of proteins. In addition to experimental techniques, computational methods, such as molecular dynamics (MD) simulations, have become an integral part in studies related to proteinligand interactions. The computational approach introduces a dynamic view of molecular interactions, and enables detailed structure-function studies. In addition, it may facilitate the estimation of binding affinities and help in identifying ligand-binding sites in proteins. In this thesis three pharmacologically important protein targets were studied with both computational and experimental methods: 1) ionotropic glutamate receptors (iGluRs), 2) filamin A (FLNa), and 3) T-cell protein tyrosine phosphatase (TCPTP). iGluRs mediate synaptic transmission in the nervous system and are linked to many neurological disorders. Partial agonism of the ligand binding domains (LBD) for these receptors was studied with MD simulations and the molecular mechanics generalised Born surface area (MM-GBSA) method. A previously unobserved intermediate closure stage for the GluN1 receptor subtype was identified, and new information about the closure mechanism was obtained. FLNa is an actin cross-linking protein linked to many cellular functions via its numerous binding partners. MM-GBSA calculations of binding free energy were shown to correlate well with the experimental data. Thus, ligands could be ranked based on their binding affinity, suggesting that also the rational design of FLNa-binding peptide mimetics would be conceivable. TCPTP is a ubiquitously expressed non-transmembrane phosphatase that negatively regulates many cancer-related kinases. TCPTP is normally autoinhibited, but several agonist molecules are known to activate it. Here, a putative binding site for TCPTP activators was identified and important structural determinants for novel activators were recognised. As TCPTP is not down-regulated in cancer cells, it is a promising target for tumor suppression. UNIVERSITY

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Dynamics of Cleft Closure of the GluA2 Ligand-binding Domain in the Presence of Full and Partial Agonists Revealed by Hydrogen-Deuterium Exchange

Cited by 27 publications

References 31 publications

Reduced Curvature of Ligand-Binding Domain Free-Energy Surface Underlies Partial Agonism at NMDA Receptors

Reduced Curvature of Ligand-Binding Domain Free-Energy Surface Underlies Partial Agonism at NMDA Receptors

Structural Dynamics of the Glycine-binding Domain of the N-Methyl-d-Aspartate Receptor

Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone

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