Identification of Two Distinct Sites for Antagonist and Biased Agonist Binding to the Human Chemokine Receptor CXCR3

Milanos, Lampros; Saleh, Noureldin; Kling, Ralf C.; Kaindl, Jonas; Tschammer, Nuška; Clark, Timothy

doi:10.1002/ange.201607831

Cited by 7 publications

(3 citation statements)

References 22 publications

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“…Recent simulations on a variety of GPCRs have shown that the extracellular vestibule of the receptor can preorient the ligand 34−39 and thus provide a well-defined extracellular end point for docking pathways, thereby simplifying the pathsampling task, often by a form of electrostatic focusing 40 but also by a simple mechanical effect in which part of the ligand is anchored, decreasing the number of degrees of freedom to be sampled. This property of the extracellular region renders our simple CV quite effective; only a few pathways for GPCR− ligand binding are possible, the ligands find the right orientation during the sampling, and binding sites along the path are identified and characterized reliably.…”

Section: Variablementioning

confidence: 99%

“…A preliminary metadynamics simulation is used to refine the poses and determine the one with the highest binding free energy, as described previously. 40 The ligand is first unbound using a faster protocol (see Methods for details). The position on the reaction coordinate at which the ligand is completely hydrated and unbound is determined, and representative structures are extracted from the simulation for each 2 Å window along the reaction coordinate from the docked pose to the unbound state.…”

Section: ■ Computational Protocolmentioning

confidence: 99%

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An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands

Saleh

Ibrahim

Saladino

et al. 2017

J. Chem. Inf. Model.

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116

138

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A generally applicable metadynamics scheme for predicting the free-energy profile of ligand binding to G-protein coupled receptors (GPCRs) is described. A common and effective collective variable (CV) has been defined using the ideally placed and highly conserved Trp6.48 as a reference point for ligand-GPCR distance measurement and the common orientation of GPCRs in the cell membrane. Using this single CV together with well-tempered multiple-walker 2 metadynamics with a funnel-like boundary allows an efficient exploration of the entire ligandbinding path from the extracellular medium to the orthosteric binding site, including vestibule and intermediate sites. The protocol can be used with X-ray structures or high-quality homology models for the receptor and is universally applicable to agonists, antagonists, partial and reverse agonists. The root mean square error (RMSE) in predicted binding free energies for 12 diverse ligands in five receptors (a total of 23 data points) is surprisingly small (less than 1 kcal mol − 1 ).The RMSEs for simulations that use receptor X-ray structures and homology models are very similar.

show abstract

Section: Variablementioning

confidence: 99%

Section: ■ Computational Protocolmentioning

confidence: 99%

An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands

Saleh

Ibrahim

Saladino

et al. 2017

J. Chem. Inf. Model.

Self Cite

116

138

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show abstract

“…By using the multiple walker approach, which introduces several simultaneous simulations with shared potentials, metadynamics gets even more efficient. To date, metadynamics simulations have been successfully used to study GPCR-ligand interactions in a couple of cases including opioid [ 18 , 19 ], vasopressin [ 20 ], chemokine [ 21 ], or cannabinoid receptors [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study

Conrad

Söldner

Miao

et al. 2020

IJMS

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The histamine H2 receptor (H2R) plays an important role in the regulation of gastric acid secretion. Therefore, it is a main drug target for the treatment of gastroesophageal reflux or peptic ulcer disease. However, there is as of yet no 3D-structural information available hampering a mechanistic understanding of H2R. Therefore, we created a model of the histamine-H2R-Gs complex based on the structure of the ternary complex of the β2-adrenoceptor and investigated the conformational stability of this active GPCR conformation. Since the physiologically relevant motions with respect to ligand binding and conformational changes of GPCRs can only partly be assessed on the timescale of conventional MD (cMD) simulations, we also applied metadynamics and Gaussian accelerated molecular dynamics (GaMD) simulations. A multiple walker metadynamics simulation in combination with cMD was applied for the determination of the histamine binding mode. The preferential binding pose detected is in good agreement with previous data from site directed mutagenesis and provides a basis for rational ligand design. Inspection of the H2R-Gs interface reveals a network of polar interactions that may contribute to H2R coupling selectivity. The cMD and GaMD simulations demonstrate that the active conformation is retained on a μs-timescale in the ternary histamine-H2R-Gs complex and in a truncated complex that contains only Gs helix α5 instead of the entire G protein. In contrast, histamine alone is unable to stabilize the active conformation, which is in line with previous studies of other GPCRs.

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Differences between G‐Protein‐Stabilized Agonist–GPCR Complexes and their Nanobody‐Stabilized Equivalents

2017

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Protein nanobodies have been used successfully as surrogates for unstable G-proteins in order to crystallizeGprotein-coupled receptors (GPCRs) in their active states.W e used molecular dynamics (MD) simulations,i ncluding metadynamics enhanced sampling, to investigate the similarities and differences between GPCR-agonist ternary complexes with the a-subunits of the appropriate G-proteins and those with the protein nanobodies (intracellular binding partners,IBPs) used for crystallization. In two of the three receptors considered, the agonist-binding mode differs significantly between the two alternative ternary complexes.T he ternary-complex model of GPCR activation entails enhancement of ligand binding by bound IBPs:O ur results showt hat IBP-specific changes can alter the agonist binding modes and thus also the criteria for designing GPCR agonists.

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Identification of Two Distinct Sites for Antagonist and Biased Agonist Binding to the Human Chemokine Receptor CXCR3

Cited by 7 publications

References 22 publications

An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands

An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands

Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study

Differences between G‐Protein‐Stabilized Agonist–GPCR Complexes and their Nanobody‐Stabilized Equivalents

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