Hydrogen-bond networks for proton couplings in G-Protein coupled receptors

Bondar, Ana‐Nicoleta; Alfonso‐Prieto, Mercedes

doi:10.3389/fphy.2022.963716

Cited by 3 publications

(3 citation statements)

References 82 publications

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“…Our hypothesis is that dynamic water-mediated H-bond networks are central to such long-distance coupling. This hypothesis is compatible with the key role of internal water molecules and water-mediated H-bond networks in proton transporter function [44] , [45] , [46] , [47] and GPCR activation [48] , [49] , [50] , [51] , [52] .…”

Section: Introductionsupporting

confidence: 79%

Protons taken hostage: Dynamic H-bond networks of the pH-sensing GPR68

Kapur,

Baldessari,

Lazaratos

et al. 2023

Computational and Structural Biotechnology Journal

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Section: Introductionsupporting

confidence: 79%

Protons taken hostage: Dynamic H-bond networks of the pH-sensing GPR68

Kapur,

Baldessari,

Lazaratos

et al. 2023

Computational and Structural Biotechnology Journal

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“…22 For some GPCRs, the protonation states of ionizable residues displayed to affect the conformational states as shown by several studies. [23][24][25][26][27] However, to our knowledge the effects of ionizable critical residues of CCR5 was not considered in detail for its conformational heterogeneity.…”

mentioning

confidence: 99%

“…Previous studies on GPCRs indicated the effects of pH and ionization state of certain residues on active/inactive state of the receptor as already mentioned in previous paragraph. [23][24][25][26][27] Hence, it is intriguing to study the possible effect of the protonation state of a binding site residue GLU283 7.39 , whether it could lead to conformational differences especially when CCR5 is in complex with different binding partners. The protonation state of this residue could also have impacts on the design of novel CCR5 inhibitor as it is illustrated that different ligands could lead to titratable residues to be in different protonation states.…”

mentioning

confidence: 99%

Investigating the Effect of GLU283 Protonation State on the Conformational Heterogeneity of CCR5 by Molecular Dynamics Simulations

Dogan,

Durdagi

2023

Preprint

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CCR5 is one of the co-receptors for HIV-1 entry into host cells and is class A GPCR. This receptor has vital roles in the immune system and is involved in the pathogenesis of different diseases. Various studies were conducted to understand its activation mechanism including structural studies in which inactive and active states of the receptor were determined in complex with various binding partners. These determined structures provided opportunities to perform molecular dynamics simulations (MD) and analyze conformational changes observed in protein structures. The atomic level dynamical studies allow us to explore the effects of ionizable residues in the receptor. Here, our aim was to investigate the changes observed in the conformation of CCR5 when it is in complex with inhibitor maraviroc (MRV), an approved anti-HIV drug or HIV-1 envelope protein GP120 in comparison to when the receptor was in apo form. In our simulations, we considered both ionized and protonated states of ionizable binding site residue GLU2837.39 in CCR5 as the protonation state of this residue was considered ambiguously in previous studies. Our simulation results suggested that in fact, the change in the protonation state of GLU2837.39 caused interaction profiles to be different between CCR5 and its binding partners, GP120 or MRV. We observed that when the protonated state of GLU2837.39 was considered in complex with envelope protein GP120, there were substantial structural changes in CCR5 indicating it adopts more of an active-like conformation. On the other hand, CCR5 when it was in complex with MRV always adopted inactive conformation regardless of the protonation state. Hence, CCR5 coreceptor displays conformational heterogeneity not only based on its binding partner but also on the state of the protonation state of a binding site residue GLU2837.39. This outcome is also in accordance with some studies showing that GP120 binding could activate signaling pathways. Additionally, this outcome could also have critical implications for the discovery of novel CCR5 inhibitors to be used as anti-HIV drugs by in silico methods such as molecular docking since consideration of the protonated state of GLU2837.39 could be required.

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Investigating the Effect of GLU283 Protonation State on the Conformational Heterogeneity of CCR5 by Molecular Dynamics Simulations

Dogan,

Durdağı

2024

J. Chem. Inf. Model.

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CCR5 is a class A GPCR and serves as one of the coreceptors facilitating HIV-1 entry into host cells. This receptor has vital roles in the immune system and is involved in the pathogenesis of different diseases. Various studies were conducted to understand its activation mechanism, including structural studies in which inactive and active states of the receptor were determined in complex with various binding partners. These determined structures provided opportunities to perform molecular dynamics (MD) simulations and to analyze conformational changes observed in the protein structures. The atomic-level dynamic studies allow us to explore the effects of ionizable residues on the receptor. Here, our aim was to investigate the conformational changes in CCR5 when it forms a complex with either the inhibitor maraviroc (MRV), an approved anti-HIV drug, or HIV-1 envelope protein GP120, and compare these changes to the receptor's apo form. In our simulations, we considered both ionized and protonated states of ionizable binding site residue GLU283 7.39 in CCR5 as the protonation state of this residue was considered ambiguously in previous studies. Our molecular simulations results suggested that in fact, the change in the protonation state of GLU283 7.39 caused interaction profiles to be different between CCR5 and its binding partners, GP120 or MRV. We observed that when the protonated state of GLU283 7.39 was considered in complex with the envelope protein GP120, there were substantial structural changes in CCR5, indicating that it adopts a more active-like conformation. On the other hand, CCR5 in complex with MRV always adopted an inactive conformation regardless of the protonation state. Hence, the CCR5 coreceptor displays conformational heterogeneity not only depending on its binding partner but also influenced by the protonation state of the binding site binding site residue GLU283 7.39 . This outcome is also in accordance with some studies showing that GP120 binding could activate signaling pathways. This outcome could also have significant implications for discovering novel CCR5 inhibitors as anti-HIV drugs using in silico methods such as molecular docking, as it may be necessary to consider the protonated state of GLU283 7.39 .

show abstract

Hydrogen-bond networks for proton couplings in G-Protein coupled receptors

Cited by 3 publications

References 82 publications

Protons taken hostage: Dynamic H-bond networks of the pH-sensing GPR68

Protons taken hostage: Dynamic H-bond networks of the pH-sensing GPR68

Investigating the Effect of GLU283 Protonation State on the Conformational Heterogeneity of CCR5 by Molecular Dynamics Simulations

Investigating the Effect of GLU283 Protonation State on the Conformational Heterogeneity of CCR5 by Molecular Dynamics Simulations

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