scholarly journals Investigation of allosteric modulation mechanism of metabotropic glutamate receptor 1 by molecular dynamics simulations, free energy and weak interaction analysis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Qifeng Bai ◽  
Xiaojun Yao
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Interaction Analysis ◽  
Allosteric Modulation ◽  
Metabotropic Glutamate ◽  
Metabotropic Glutamate Receptor 1 ◽  
Dynamics Simulations

Exploring the binding mechanism of positive allosteric modulators in human metabotropic glutamate receptor 2 using molecular dynamics simulations

2021 ◽  
Author(s):  
Panpan Wang ◽  
Xiaonan Gao ◽  
Ke Zhang ◽  
Qinglan Pei ◽  
Xiaobo Xu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Binding Mode ◽  
Allosteric Modulators ◽  
Binding Mechanism ◽  
Metabotropic Glutamate ◽  
High Affinity ◽  
Dynamics Simulations ◽  
High Electronegativity

Based on the binding mode and electrostatics, the features of high affinity PAMs were the reduced hydrophobicity with low electronegativity of R1, increased hydrophobicity with low electronegativity of R2 and with high electronegativity of linker.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

scholarly journals Metabotropic glutamate receptor 1 is associated with unfavorable prognosis in ER-negative and triple-negative breast cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Anna E. M. Bastiaansen ◽  
A. Mieke Timmermans ◽  
Marcel Smid ◽  
Carolien H. M. van Deurzen ◽  
Esther S. P. Hulsenboom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Glutamate Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metabotropic Glutamate Receptor ◽  
Metabotropic Glutamate ◽  
Metabotropic Glutamate Receptor 1 ◽  
Novel Target ◽  
Cancer Tissues

AbstractNew therapies are an urgent medical need in all breast cancer subgroups. Metabotropic glutamate receptor 1 (mGluR1) is suggested as a potential new molecular target. We examined the prevalence mGluR1 expression in different clinically relevant breast cancer subgroups and determined its association with prognosis. In this retrospective cohort, 394 consecutive primary breast cancer tissues were incorporated into a tissue microarray and immunohistochemically stained for mGluR1. The prevalence of mGluR1 protein expression in different breast cancer subgroups was evaluated and correlated with metastasis-free survival (MFS) and overall survival (OS). In total, 56% (n = 219) breast cancer tissues had mGluR1 expression. In estrogen receptor (ER)-negative tumors, 31% (n = 18/58) had mGluR1 expression that was significantly associated with MFS (HR 5.00, 95% CI 1.03–24.35, p = 0.046) in multivariate analysis, independently from other prognostic factors. Of the 44 triple-negative breast cancer (TNBC), 25% (n = 11) expressed mGluR1. mGluR1 expression in TNBC was significantly associated with shorter MFS (HR 8.60, 95% CI 1.06–20.39, p = 0.044) and with poor OS (HR 16.07, 95% CI 1.16–223.10, p = 0.039). In conclusion, mGluR1 is frequently expressed in breast cancer. In ER-negative breast cancer and in TNBC mGluR1 protein expression is an unfavorable prognostic marker. This study provides rationale to explore mGluR1 as a novel target for breast cancer treatment, especially for the more aggressive TNBC.

scholarly journals Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1

2012 ◽  
Vol 91 (3) ◽  
pp. 553-564 ◽  
Author(s):  
Velina Guergueltcheva ◽  
Dimitar N. Azmanov ◽  
Dora Angelicheva ◽  
Katherine R. Smith ◽  
Teodora Chamova ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Glutamate Receptor ◽  
Autosomal Recessive ◽  
Metabotropic Glutamate Receptor ◽  
Metabotropic Glutamate ◽  
Metabotropic Glutamate Receptor 1
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