当前位置： SCI文献检索 > Journal of Chemical Information and Modeling期刊下所有文献 > Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT1R Initiated by van der Waals Attraction.

Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT1R Initiated by van der Waals Attraction.

Abstract：

:We present a succession of structural changes involved in hormone peptide activation of a prototypical GPCR. Microsecond molecular dynamics simulation generated conformational ensembles reveal propagation of structural changes through key "microswitches" within human AT1R bound to native hormone. The endocrine octa-peptide angiotensin II (AngII) activates AT1R signaling in our bodies which maintains physiological blood pressure, electrolyte balance, and cardiovascular homeostasis. Excessive AT1R activation is associated with pathogenesis of hypertension and cardiovascular diseases which are treated by sartan drugs. The mechanism of AT1R inhibition by sartans has been elucidated by 2.8 Å X-ray structures, mutagenesis, and computational analyses. Yet, the mechanism of AT1R activation by AngII is unclear. The current study delineates an activation scheme initiated by AngII binding. A van der Waals "grasp" interaction between Phe8AngII with Ile2887.39 in AT1R induced mechanical strain pulling Tyr2927.43 and breakage of critical interhelical H-bonds, first between Tyr2927.43 and Val1083.32 and second between Asn1113.35 and Asn2957.46. Subsequently changes are observed in conserved microswitches DRYTM3, Yx7K(R)TM5, CWxPTM6, and NPxxYTM7 in AT1R. Activating the microswitches in the intracellular region of AT1R may trigger formation of the G-protein binding pocket as well as exposure of helix-8 to cytoplasm. Thus, the active-like conformation of AT1R is initiated by the van der Waals interaction of Phe8AngII with Ile2887.39, followed by systematic reorganization of critical interhelical H-bonds and activation of microswitches.

journal_name

J Chem Inf Model

journal_title

Journal of chemical information and modeling

authors

Singh KD,Unal H,Desnoyer R,Karnik SS

doi

10.1021/acs.jcim.8b00583

subject

Has Abstract

pub_date

2019-01-28 00:00:00

pages

373-385

issue

1

eissn

1549-9596

issn

1549-960X

journal_volume

59

pub_type

杂志文章

相关文献

Journal of Chemical Information and Modeling文献大全
  • Exploring inhibitor release pathways in histone deacetylases using random acceleration molecular dynamics simulations.

    abstract：:Molecular channel exploration perseveres to be the prominent solution for eliciting structure and accessibility of active site and other internal spaces of macromolecules. The volume and silhouette characterization of these channels provides answers for the issues of substrate access and ligand swapping between the ob...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci200584f

    authors： Kalyaanamoorthy S,Chen YP

    更新日期：2012-02-27 00:00:00

  • PIIMS Server: A Web Server for Mutation Hotspot Scanning at the Protein-Protein Interface.

    abstract：:Protein-protein interactions (PPIs) play vital roles in regulating biological processes, such as cellular and signaling pathways. Hotspots are certain residues located at protein-protein interfaces that contribute more in protein-protein binding than other residues. Research on the mutational effects of hotspots is im...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.0c00966

    authors： Wu FX,Yang JF,Mei LC,Wang F,Hao GF,Yang GF

    更新日期：2021-01-25 00:00:00

  • How Well Does the Extended Linear Interaction Energy Method Perform in Accurate Binding Free Energy Calculations?

    abstract：:With continually increased computer power, molecular mechanics force field-based approaches, such as the endpoint methods of molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and molecular mechanics generalized Born surface area (MM-GBSA), have been routinely applied in both drug lead identification and opt...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.0c00934

    authors： Hao D,He X,Ji B,Zhang S,Wang J

    更新日期：2020-12-28 00:00:00

  • ChemSchematicResolver: A Toolkit to Decode 2D Chemical Diagrams with Labels and R-Groups into Annotated Chemical Named Entities.

    abstract：:The number of journal articles in the scientific domain has grown to the point where it has become impossible for researchers to capitalize on all findings in their relevant discipline. Information is stored in these articles in a number of ways, including figures that describe important results. In organic chemistry,...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.0c00042

    authors： Beard EJ,Cole JM

    更新日期：2020-04-27 00:00:00

  • Statistical Analysis on the Performance of Molecular Mechanics Poisson-Boltzmann Surface Area versus Absolute Binding Free Energy Calculations: Bromodomains as a Case Study.

    abstract：:Binding free energy calculations that make use of alchemical pathways are becoming increasingly feasible thanks to advances in hardware and algorithms. Although relative binding free energy (RBFE) calculations are starting to find widespread use, absolute binding free energy (ABFE) calculations are still being explore...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.7b00347

    authors： Aldeghi M,Bodkin MJ,Knapp S,Biggin PC

    更新日期：2017-09-25 00:00:00

  • A Coarse-Grained Force Field Parameterized for MgCl2 and CaCl2 Aqueous Solutions.

    abstract：:Calcium and magnesium ions play important roles in many physicochemical processes. To facilitate the investigation of phenomena related to these ions that occur over large length and time scales, a coarse-grained force field (CGFF) is developed for MgCl2 and CaCl2 aqueous solutions. The ions are modeled by CG beads wi...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.7b00206

    authors： Gong Z,Sun H

    更新日期：2017-07-24 00:00:00

  • Influence of Descriptor Implementation on Compound Ranking Based on Multiparameter Assessment.

    abstract：:Most of the common molecular descriptors have numerous different implementations. This can influence the results of compound prioritization based on the multiparameter assessment (MPA) approach that allows a medicinal chemist to simultaneously analyze and achieve the desired balance of the diverse and often conflictin...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.7b00734

    authors： Sosnina EA,Osolodkin DI,Radchenko EV,Sosnin S,Palyulin VA

    更新日期：2018-05-29 00:00:00

  • How Reactive are Druggable Cysteines in Protein Kinases?

    abstract：:Targeted covalent inhibitors (TCIs) have been successfully developed as high-affinity and selective inhibitors of enzymes of the protein kinase family. These drugs typically act by undergoing an electrophilic addition with an active-site cysteine residue, so design of a TCI begins with the identification of a "druggab...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.8b00454

    authors： Awoonor-Williams E,Rowley CN

    更新日期：2018-09-24 00:00:00

  • Accurate Estimation of pKb Values for Amino Groups from Surface Electrostatic Potential (VS,min) Calculations: The Isoelectric Points of Amino Acids as a Case Study.

    abstract：:Theoretical calculation of equilibrium dissociation constants is a very computationally demanding and time-consuming process since it requires an extremely accurate computation of the solvation free energy changes for each of the species involved. By correlating the minimum surface electrostatic potential (VS,min) on ...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.9b01173

    authors： Sandoval-Lira J,Mondragón-Solórzano G,Lugo-Fuentes LI,Barroso-Flores J

    更新日期：2020-03-23 00:00:00

  • PyCGTOOL: Automated Generation of Coarse-Grained Molecular Dynamics Models from Atomistic Trajectories.

    abstract：:Development of coarse-grained (CG) molecular dynamics models is often a laborious process which commonly relies upon approximations to similar models, rather than systematic parametrization. PyCGTOOL automates much of the construction of CG models via calculation of both equilibrium values and force constants of inter...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.7b00096

    authors： Graham JA,Essex JW,Khalid S

    更新日期：2017-04-24 00:00:00

  • Comparison of several molecular docking programs: pose prediction and virtual screening accuracy.

    abstract：:Molecular docking programs are widely used modeling tools for predicting ligand binding modes and structure based virtual screening. In this study, six molecular docking programs (DOCK, FlexX, GLIDE, ICM, PhDOCK, and Surflex) were evaluated using metrics intended to assess docking pose and virtual screening accuracy. ...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci900056c

    authors： Cross JB,Thompson DC,Rai BK,Baber JC,Fan KY,Hu Y,Humblet C

    更新日期：2009-06-01 00:00:00

  • New serotonin 5-HT(6) ligands from common feature pharmacophore hypotheses.

    abstract：:Serotonin 5-HT6 receptor antagonists are thought to play an important role in the treatment of psychiatry, Alzheimer's disease, and probably obesity. To find novel and potent 5-HT6 antagonists and to provide a new idea for drug design, we used a ligand-based pharmacophore to perform the virtual screening of a commerci...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci700160t

    authors： Kim HJ,Doddareddy MR,Choo H,Cho YS,No KT,Park WK,Pae AN

    更新日期：2008-01-01 00:00:00

  • Evaluation of Generalized Born Models for Large Scale Affinity Prediction of Cyclodextrin Host-Guest Complexes.

    abstract：:Binding affinity prediction with implicit solvent models remains a challenge in virtual screening for drug discovery. In order to assess the predictive power of implicit solvent models in docking techniques with Amber scoring, three generalized Born models (GBHCT, GBOBCI, and GBOBCII) available in Dock 6.7 were utiliz...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.6b00418

    authors： Zhang H,Yin C,Yan H,van der Spoel D

    更新日期：2016-10-24 00:00:00

  • Ligand-based virtual screening approach using a new scoring function.

    abstract：:In this study, we aimed to develop a new ligand-based virtual screening approach using an effective shape-overlapping procedure and a more robust scoring function (denoted by the HWZ score for convenience). The HWZ score-based virtual screening approach was tested against the compounds for 40 protein targets available...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci200617d

    authors： Hamza A,Wei NN,Zhan CG

    更新日期：2012-04-23 00:00:00

  • Assessing the Conformational Equilibrium of Carboxylic Acid via Quantum Mechanical and Molecular Dynamics Studies on Acetic Acid.

    abstract：:Accurate hydrogen placement in molecular modeling is crucial for studying the interactions and dynamics of biomolecular systems. The carboxyl functional group is a prototypical example of a functional group that requires protonation during structure preparation. To our knowledge, when in their neutral form, carboxylic...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.8b00835

    authors： Lim VT,Bayly CI,Fusti-Molnar L,Mobley DL

    更新日期：2019-05-28 00:00:00

  • Rigidity Strengthening: A Mechanism for Protein-Ligand Binding.

    abstract：:Protein-ligand binding is essential to almost all life processes. The understanding of protein-ligand interactions is fundamentally important to rational drug and protein design. Based on large scale data sets, we show that protein rigidity strengthening or flexibility reduction is a mechanism in protein-ligand bindin...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.7b00226

    authors： Nguyen DD,Xiao T,Wang M,Wei GW

    更新日期：2017-07-24 00:00:00

  • Probing the Binding Pathway of BRACO19 to a Parallel-Stranded Human Telomeric G-Quadruplex Using Molecular Dynamics Binding Simulation with AMBER DNA OL15 and Ligand GAFF2 Force Fields.

    abstract：:Human telomeric DNA G-quadruplex has been identified as a good therapeutic target in cancer treatment. G-quadruplex-specific ligands that stabilize the G-quadruplex have great potential to be developed as anticancer agents. Two crystal structures (an apo form of parallel stranded human telomeric G-quadruplex and its h...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.7b00287

    authors： Machireddy B,Kalra G,Jonnalagadda S,Ramanujachary K,Wu C

    更新日期：2017-11-27 00:00:00

  • Molecular Simulation of αvβ6 Integrin Inhibitors.

    abstract：:The urgent need for new treatments for the chronic lung disease idiopathic pulmonary fibrosis (IPF) motivates research into antagonists of the RGD binding integrin αvβ6, a protein linked to the initiation and progression of the disease. Molecular dynamics (MD) simulations of αvβ6 in complex with its natural ligand, pr...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.0c00254

    authors： Guest EE,Oatley SA,Macdonald SJF,Hirst JD

    更新日期：2020-11-23 00:00:00

  • Support vector regression scoring of receptor-ligand complexes for rank-ordering and virtual screening of chemical libraries.

    abstract：:The community structure-activity resource (CSAR) data sets are used to develop and test a support vector machine-based scoring function in regression mode (SVR). Two scoring functions (SVR-KB and SVR-EP) are derived with the objective of reproducing the trend of the experimental binding affinities provided within the ...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci200078f

    authors： Li L,Wang B,Meroueh SO

    更新日期：2011-09-26 00:00:00

  • The ensemble performance index: an improved measure for assessing ensemble pose prediction performance.

    abstract：:We present a theoretical study on the performance of ensemble docking methodologies considering multiple protein structures. We perform a theoretical analysis of pose prediction experiments which is completely unbiased, as we make no assumptions about specific scoring functions, search paradigms, protein structures, o...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci2002796

    authors： Korb O,McCabe P,Cole J

    更新日期：2011-11-28 00:00:00

  • Structure-based approach for the study of estrogen receptor binding affinity and subtype selectivity.

    abstract：:Estrogens exert important physiological effects through the modulation of two human estrogen receptor (hER) subtypes, alpha (hERalpha) and beta (hERbeta). Because the levels and relative proportion of hERalpha and hERbeta differ significantly in different target cells, selective hER ligands could target specific tissu...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci8002182

    authors： Salum LB,Polikarpov I,Andricopulo AD

    更新日期：2008-11-01 00:00:00

  • RDChiral: An RDKit Wrapper for Handling Stereochemistry in Retrosynthetic Template Extraction and Application.

    abstract：:There is a renewed interest in computer-aided synthesis planning, where the vast majority of approaches require the application of retrosynthetic reaction templates. Here we introduce RDChiral, an open-source Python wrapper for RDKit designed to provide consistent handling of stereochemical information in applying ret...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.9b00286

    authors： Coley CW,Green WH,Jensen KF

    更新日期：2019-06-24 00:00:00

  • LiCABEDS II. Modeling of ligand selectivity for G-protein-coupled cannabinoid receptors.

    abstract：:The cannabinoid receptor subtype 2 (CB2) is a promising therapeutic target for blood cancer, pain relief, osteoporosis, and immune system disease. The recent withdrawal of Rimonabant, which targets another closely related cannabinoid receptor (CB1), accentuates the importance of selectivity for the development of CB2 ...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci3003914

    authors： Ma C,Wang L,Yang P,Myint KZ,Xie XQ

    更新日期：2013-01-28 00:00:00

  • Influence of protonation, tautomeric, and stereoisomeric states on protein-ligand docking results.

    abstract：:In this work, we present a systematical investigation of the influence of ligand protonation states, stereoisomers, and tautomers on results obtained with the two protein-ligand docking programs GOLD and PLANTS. These different states were generated with a fully automated tool, called SPORES (Structure PrOtonation and...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci800420z

    authors： ten Brink T,Exner TE

    更新日期：2009-06-01 00:00:00

  • Modeling compound-target interaction network of traditional Chinese medicines for type II diabetes mellitus: insight for polypharmacology and drug design.

    abstract：:In this study, in order to elucidate the action mechanism of traditional Chinese medicines (TCMs) that exhibit clinical efficacy for type II diabetes mellitus (T2DM), an integrated protocol that combines molecular docking and pharmacophore mapping was employed to find the potential inhibitors from TCM for the T2DM-rel...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci400146u

    authors： Tian S,Li Y,Li D,Xu X,Wang J,Zhang Q,Hou T

    更新日期：2013-07-22 00:00:00

  • Comparison Study of Polar and Nonpolar Contributions to Solvation Free Energy.

    abstract：:In this study, we compared the contributions of polar and nonpolar interactions to the solvation free energy of a solute in solvent, which is decomposed into four different terms based on the nature of interactions: (i) electrostatic solvation free energy term counting for the work done to move solute charges from fix...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.7b00368

    authors： Izairi R,Kamberaj H

    更新日期：2017-10-23 00:00:00

  • Pushing the Limits of Computational Structure-Based Drug Design with a Cryo-EM Structure: The Ca2+ Channel α2δ-1 Subunit as a Test Case.

    abstract：:Cryo-electron microscopy (cryo-EM) is emerging as a real alternative for structural elucidation. In spite of this, very few cryo-EM structures have been described so far as successful platforms for in silico drug design. Gabapentin and pregabalin are some of the most successful drugs in the treatment of epilepsy and n...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.8b00347

    authors： Kotev M,Pascual R,Almansa C,Guallar V,Soliva R

    更新日期：2018-08-27 00:00:00

  • Binding Interactions of Ergotamine and Dihydroergotamine to 5-Hydroxytryptamine Receptor 1B (5-HT1b) Using Molecular Dynamics Simulations and Dynamic Network Analysis.

    abstract：:Ergotamine (ERG) and dihydroergotamine (DHE), common migraine drugs, have small structural differences but lead to clinically important distinctions in their pharmacological profiles. For example, DHE is less potent than ERG by about 10-fold at the 5-hydroxytrptamine receptor 1B (5-HT1B). Although the high-resolution ...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.9b01082

    authors： Sullivan HJ,Tursi A,Moore K,Campbell A,Floyd C,Wu C

    更新日期：2020-03-23 00:00:00

  • Structure-activity relationships in non-ligand binding pocket (non-LBP) diarylhydrazide antiandrogens.

    abstract：:We report the synthesis and a study of the structure-activity relationships of a new series of diarylhydrazides as potential selective non-ligand binding pocket androgen receptor antagonists. Their biological activity as antiandrogens in the context of the development of treatments for castration resistant prostate ca...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci400189m

    authors： Caboni L,Egan B,Kelly B,Blanco F,Fayne D,Meegan MJ,Lloyd DG

    更新日期：2013-08-26 00:00:00

  • Time-Domain Analysis of Molecular Dynamics Trajectories Using Deep Neural Networks: Application to Activity Ranking of Tankyrase Inhibitors.

    abstract：:Molecular dynamics simulations provide valuable insights into the behavior of molecular systems. Extending the recent trend of using machine learning techniques to predict physicochemical properties from molecular dynamics data, we propose to consider the trajectories as multidimensional time series represented by 2D ...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.9b00135

    authors： Berishvili VP,Perkin VO,Voronkov AE,Radchenko EV,Syed R,Venkata Ramana Reddy C,Pillay V,Kumar P,Choonara YE,Kamal A,Palyulin VA

    更新日期：2019-08-26 00:00:00